U.S. patent application number 15/716098 was filed with the patent office on 2018-04-19 for methods of treatment comprising administering a high daily dose of oxycodone and naloxone in a 2:1 weight ratio.
The applicant listed for this patent is Euro-Celtique S. A.. Invention is credited to Michael HOPP, Wolfram Kremers, Petra Leyendecker.
Application Number | 20180104236 15/716098 |
Document ID | / |
Family ID | 59966773 |
Filed Date | 2018-04-19 |
United States Patent
Application |
20180104236 |
Kind Code |
A1 |
HOPP; Michael ; et
al. |
April 19, 2018 |
METHODS OF TREATMENT COMPRISING ADMINISTERING A HIGH DAILY DOSE OF
OXYCODONE AND NALOXONE IN A 2:1 WEIGHT RATIO
Abstract
The present invention relates to methods of treatment
comprising, inter alia, administering a high daily dose of
oxycodone, such as a daily dose of at least 90 mg oxycodone, and
naloxone in a 2:1 weight ratio to a patient in need thereof.
Inventors: |
HOPP; Michael; (Bad Camberg,
DE) ; Leyendecker; Petra; (Braunfels, DE) ;
Kremers; Wolfram; (Bad Honnef, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Euro-Celtique S. A. |
Luxembourg |
|
LU |
|
|
Family ID: |
59966773 |
Appl. No.: |
15/716098 |
Filed: |
September 26, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62462772 |
Feb 23, 2017 |
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62399968 |
Sep 26, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/10 20180101; A61K
31/485 20130101; A61K 2300/00 20130101; A61P 25/04 20180101; A61K
31/485 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61P 1/10 20060101 A61P001/10; A61P 25/04 20060101
A61P025/04 |
Claims
1. A method of improving, maintaining, or normalizing bowel
function in a patient on opioid therapy comprising orally
administering the patient a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
wherein the daily dose comprises at least 90 mg of the oxycodone or
pharmaceutically acceptable salt thereof; and the daily dose is
administered as two or more prolonged release oral dosage
forms.
2. (canceled)
3. A method of treating pain comprising orally administering to a
patient in need thereof a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
wherein the daily dose comprises at least 90 mg of the oxycodone or
pharmaceutically acceptable salt thereof; the daily dose is
administered as two or more prolonged release oral dosage forms;
and the method improves, maintains, or normalizes the bowel
function of the patient.
4. The method of claim 3, wherein the improvement in, maintenance
of, or normalization of bowel function is assessed by the
difference in bowel function index (BFI) scores following
administering the daily dose and a corresponding naloxone-free
daily dose, and wherein the difference in BFI scores is at least
12.
5-6. (canceled)
7. The method of claim 4, wherein the difference in BFI scores is
at least 18.
8. The method of claim 4, wherein the BFI scores are measured by
taking the mean symptom scores of ease of defecation, feeling of
incomplete bowel evacuation, and judgment of constipation.
9. The method of claim 3, wherein improving maintaining, or
normalizing bowel function comprises reducing or preventing
opioid-induced constipation.
10-14. (canceled)
15. A method of treating breakthrough pain in a patient while
treating chronic pain and maintaining bowel function in the patient
comprising orally administering to the patient immediate release
oxycodone without an opioid antagonist for treating breakthrough
pain; wherein the chronic pain is treated by orally administering
to the patient a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
wherein the daily dose comprises at least 90 mg of the oxycodone or
pharmaceutically acceptable salt thereof; wherein the daily dose is
administered as two or more prolonged release oral dosage
forms.
16-27. (canceled)
28. The method of claim 3, wherein the patient is suffering from
cancer.
29. (canceled)
30. The method of claim 3, wherein subsequent to the method the
patient's BFI score is 35 or less.
31-32. (canceled)
33. The method of claim 30, wherein subsequent to the method the
patient's BFI score is 29 or less.
34. The method of claim 3, wherein the daily dose comprises 100 mg
to 160 mg of the oxycodone or pharmaceutically acceptable salt
thereof.
35. The method of claim 3, wherein the daily dose comprises 130 mg
to 200 mg of the oxycodone or pharmaceutically acceptable salt
thereof.
36. (canceled)
37. The method of claim 3, wherein the daily dose comprises 90 mg,
110 mg, 130, mg, 150 mg, 170 mg, or 190, mg of the oxycodone or
pharmaceutically acceptable salt thereof.
38. The method of claim 3, wherein the daily dose comprises 100 mg,
120 mg, 140 mg, 160 mg, 180 mg, or 200 mg of the oxycodone or
pharmaceutically acceptable salt thereof.
39. The method of claim 3, wherein the daily dose comprises 120 mg,
160 mg, or 200 mg of the oxycodone or pharmaceutically acceptable
salt thereof.
40-49. (canceled)
50. The method of claim 3, wherein the prolonged release oral
dosage forms are administered at 12 hour intervals.
51-59. (canceled)
60. The method of claim 3, wherein the daily dose is administered
daily for a period of at least 4 weeks.
61. The method of claim 3, wherein the daily dose is administered
daily for a period of at least 5 weeks.
62. The method of claim 3, wherein the daily dose is administered
daily for a period of at least 8 weeks.
63. The method of claim 3, wherein the daily dose is administered
daily for a period of at least 24 weeks.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to methods of treatment
comprising, inter alia, administering a high daily dose of
oxycodone, such as a daily dose of at least 90 mg oxycodone, and
naloxone in a 2:1 weight ratio to a patient in need thereof.
BACKGROUND OF THE INVENTION
[0002] Oxycodone/naloxone prolonged release (OXN PR) is an oral
prolonged-release formulation containing oxycodone and naloxone in
a 2:1 ratio. This fixed combination has been shown to provide
sufficient analgesic effect of oxycodone but with an improved
safety profile (Meissner et al., Eur. J. Pain, 13, 56-64 (2009)).
The product was released in Germany in 2006 and is now available,
inter alia, in different European countries in different dose
strengths for twice-daily use. OXN PR uses the opioid antagonist
naloxone to maintain bowel function by counteracting opioid-induced
constipation (OIC) by blocking the action of oxycodone at
opioid-receptors locally in the gut. For many years, the highest
dosage strength approved by regulatory authorities was the
twice-daily use of the OXN 40/20 PR tablet resulting in daily doses
of oxycodone of 80 mg and of naloxone of 40 mg (OXN 80/40 PR).
[0003] However, it was found that when a patient's pain was very
strong, there was a need for daily doses higher than the
above-mentioned maximum approved daily dose of OXN 80/40 PR. In
order to achieve sufficient analgesia for such situations, patients
were often instructed to take a daily dose of up to 400 mg
oxycodone prolonged release (OxyPR) in addition to the maximum OXN
dose.
[0004] Physicians considered that this extra dosing of oxycodone
might impair the beneficial bowel function and OIC effects of OXN,
and so there remained a need for providing higher levels of
analgesia that did not lead to a worsening of bowel function or
OIC. Unfortunately, initial results of the study by Meissner et
al., 2009 were interpreted as pointing towards a decrease of OXN's
positive bowel function and OIC effects if daily doses higher than
OXN 80/40 would be administered (see in particular FIG. 6 of
Meissner et al., 2009). This meant that patients suffering from
intense pain and in need of large daily doses of opioid analgesics
would be unable to use such treatment regimens without suffering
from loss of bowel function and debilitating OIC.
[0005] Cancer patients frequently suffer from various bowel
dysfunction symptoms--such as abdominal discomfort, nausea,
vomiting, and especially constipation--that are a result of their
disease state and associated cancer treatment. The intense pain
from cancer often leaves such patients in need of the strong pain
relief afforded by opioid analgesics, but studies have demonstrated
that such patients often forego adequate pain relief and endure a
lower quality of life because of the disruption in bowel function
and OIC associated with opioids (Cuomo et al., Am. J. Hosp.
Palliat. Med., 31(8) 867-876 (2014) (1998)). Cancer patients are
more susceptible to opioid-induced bowel dysfunction and
constipation at least because they are already experiencing bowel
dysfunction from their cancer and cancer treatment and because they
typically require high daily doses of strong opioids, and such high
daily doses were known to produce more bowel dysfunction and OIC
than lower daily doses (Sykes, N. P., Palliat. Med., 12, 375-382
(1998)).
[0006] The present disclosure has surprisingly found that the
potential worsening of bowel function and OIC at daily OXN doses
higher than 80/40 does not occur and that such higher OXN amounts
can be administered to patients in need of high levels of pain
relief, such as cancer patients, while still providing a clinically
significant effect on their bowel function.
OBJECTS AND SUMMARY OF THE INVENTION
[0007] It is an object of certain embodiments of the present
invention to provide methods of improving bowel function, such as
reducing or preventing opioid-induced constipation.
[0008] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
improving bowel function comprising orally administering to a
patient in need thereof a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
[0009] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0010] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0011] It is an object of certain embodiments of the present
invention to provide methods of treating pain and improving bowel
function, such as reducing or preventing opioid-induced
constipation.
[0012] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
treating pain and improving bowel function comprising orally
administering to a patient in need thereof a daily dose comprising
oxycodone or a pharmaceutically acceptable salt thereof and
naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0013] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0014] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0015] It is an object of certain embodiments of the present
invention to provide methods of maintaining bowel function in a
patient on opioid therapy.
[0016] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
maintaining bowel function in a patient on opioid therapy
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0017] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0018] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0019] It is an object of certain embodiments of the present
invention to provide methods of treating pain and maintaining bowel
function.
[0020] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
treating pain and maintaining bowel function in a patient
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0021] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0022] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0023] It is an object of certain embodiments of the present
invention to provide methods of treating breakthrough pain in a
patient on opioid therapy.
[0024] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
treating breakthrough pain in a patient on opioid therapy while
maintaining bowel function comprising orally administering to the
patient immediate release oxycodone without an opioid
antagonist;
[0025] wherein the opioid therapy comprises orally administering to
the patient a daily dose comprising oxycodone or a pharmaceutically
acceptable salt thereof and naloxone or a pharmaceutically
acceptable salt thereof in a 2:1 weight ratio;
[0026] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof;
[0027] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0028] It is an object of certain embodiments of the present
invention to provide methods for treating breakthrough pain in a
patient while treating chronic pain.
[0029] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
treating breakthrough pain in a patient while treating chronic pain
and maintaining bowel function in the patient comprising orally
administering to the patient immediate release oxycodone without an
opioid antagonist for treating breakthrough pain;
[0030] wherein the chronic pain is treated by orally administering
to the patient a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
[0031] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof;
[0032] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0033] It is an object of certain embodiments of the present
invention to provide methods for normalizing bowel function in a
patient on opioid therapy.
[0034] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
normalizing bowel function in a patient on opioid therapy
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0035] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0036] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0037] It is an object of certain embodiments of the present
invention to provide methods for treating pain and normalizing
bowel function in a patient.
[0038] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
treating pain and normalizing bowel function in a patient
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0039] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0040] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0041] It is an object of certain embodiments of the present
invention to provide methods for treating pain in a patient
suffering from cancer.
[0042] The above object and others can be achieved by the present
invention, which in certain embodiments is directed to a method of
treating pain in a patient suffering from cancer comprising orally
administering to the patient a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
[0043] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0044] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0045] The above embodiments disclose their subject matter as
"methods of treatment". It is noted that the corresponding subject
matter may also be formulated differently, e.g. as "for use in
treating". The "for use in treating" wording is given for the
subject matter of the above embodiments in the following (it is
noted that such a wording may of course also be used for the
subject matter of all further embodiments given in this application
below):
[0046] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in improving bowel function, wherein the daily dose is
administered orally and wherein the daily dose is administered as
two or more prolonged release oral dosage forms.
[0047] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in treating pain and improving bowel function, wherein the
daily dose is administered orally and wherein the daily dose is
administered as two or more prolonged release oral dosage
forms.
[0048] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in maintaining bowel function in a patient on opioid therapy,
wherein the daily dose is administered orally and wherein the daily
dose is administered as two or more prolonged release oral dosage
forms.
[0049] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in treating pain and maintaining bowel function, wherein the
daily dose is administered orally and wherein the daily dose is
administered as two or more prolonged release oral dosage
forms.
[0050] Immediate release oxycodone for use in treating breakthrough
pain in a patient on opioid therapy while maintaining bowel
function, wherein the immediate release oxycodone is administered
without an opioid antagonist, wherein the opioid therapy comprises
orally administering a daily dose comprising at least 90 mg of
oxycodone or a pharmaceutically acceptable salt thereof and
naloxone or a pharmaceutical acceptable salt thereof in a 2:1
weight ratio, and wherein the daily dose is administered as two or
more prolonged release oral dosage forms.
[0051] Immediate release oxycodone for use in treating breakthrough
pain while treating chronic pain and maintaining bowel function,
wherein the immediate release oxycodone is administered without an
opioid antagonist, wherein the chronic pain is treated by orally
administering a daily dose comprising at least 90 mg of oxycodone
or a pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio, and
wherein the daily dose is administered as two or more prolonged
release oral dosage forms.
[0052] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in normalizing bowel function in a patient on opioid therapy,
wherein the daily dose is administered orally and wherein the daily
dose is administered as two or more prolonged release oral dosage
forms.
[0053] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in treating pain and normalizing bowel function, wherein the
daily dose is administered orally and wherein the daily dose is
administered as two or more prolonged release oral dosage
forms.
[0054] A daily dose comprising at least 90 mg of oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutical acceptable salt thereof in a 2:1 weight ratio for
use in treating pain in a patient suffering from cancer, wherein
the daily dose is administered orally and wherein the daily dose is
administered as two or more prolonged release oral dosage
forms.
[0055] The methods disclosed herein may also be understood as the
corresponding "use in the manufacture of a medicament" (so-called
"Swiss-type" language).
BRIEF DESCRIPTION OF THE DRAWINGS
[0056] FIG. 1 is a graphical depiction of the study design of
Example 1.
[0057] FIG. 2 shows the consort flow diagram.
[0058] FIG. 3A and FIG. 3B show the results of the BFI in the full
analysis populations for (A) the total study group and (B) the
cancer subgroup.
[0059] FIG. 4A and FIG. 4B show the pain scores for (A) the total
study group and (B) the cancer subgroup.
[0060] FIG. 5 shows the Bowel Function Index in the extension phase
described in Example 2--Observed Values: Total Exposure Safety
Population.
[0061] FIG. 6 shows the Bowel Function Index in the extension phase
described in Example 2--Observed Values by Core Phase Treatment:
Total Exposure Safety Population.
[0062] FIG. 7 shows the average pain over the last 24 hours in the
extension phase described in Example 2--Observed Values: Total
Exposure Safety Population.
DETAILED DESCRIPTION
[0063] In certain embodiments, the present disclosure provides a
method of improving bowel function comprising orally administering
to a patient in need thereof a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
[0064] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0065] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0066] In some embodiments, the present disclosure provides a
method of treating pain and improving bowel function comprising
orally administering to a patient in need thereof a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0067] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0068] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0069] In certain embodiments, the present disclosure provides a
method of maintaining bowel function in a patient on opioid therapy
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0070] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0071] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0072] In some embodiments, the present disclosure provides a
method of treating pain and maintaining bowel function in a patient
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0073] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0074] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0075] In certain embodiments, the present disclosure provides a
method of treating breakthrough pain in a patient on opioid therapy
while maintaining bowel function comprising orally administering to
the patient immediate release oxycodone without an opioid
antagonist;
[0076] wherein the opioid therapy comprises orally administering to
the patient a daily dose comprising oxycodone or a pharmaceutically
acceptable salt thereof and naloxone or a pharmaceutically
acceptable salt thereof in a 2:1 weight ratio;
[0077] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof;
[0078] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0079] In some embodiments, the present disclosure provides a
method of treating breakthrough pain in a patient while treating
chronic pain and maintaining bowel function in the patient
comprising orally administering to the patient immediate release
oxycodone without an opioid antagonist for treating breakthrough
pain;
[0080] wherein the chronic pain is treated by orally administering
to the patient a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio;
[0081] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof;
[0082] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0083] In particular embodiments of the above methods of treating
breakthrough pain, the patient is administered the immediate
release oxycodone, without an opioid antagonist, for treating
breakthrough pain in a dose per day that is equivalent to 10% to
120% of the oxycodone in the daily dose, such as equivalent to 5%,
10%, 12%, 15%, 17%, 20%, 25%, 30%, or 35% to 50%, 60%, 70%, 80%,
90%, 100%, 110%, or 120% of the oxycodone in the daily dose per
day. For example, the patient may be administered the immediate
release oxycodone in a dose per day that is equivalent to 10% to
120%, 15% to 100%, 17% to 80%, or 20 to 70%, such as about 20%,
25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 110%, or 120% of
the oxycodone in the daily dose. In certain embodiments, the
patient is administered the immediate release oxycodone in a dose
that is equivalent to 1/8, 1/6, 1/4, 1/3, or 1/2 of the oxycodone
in the daily dose. In some embodiments, the patient is administered
the immediate release oxycodone once-a-day, or multiple times a
day, such as 2, 3, 4, 5, 6, 7, or 8 times per day or up to 2, 3, 4,
5, 6, 7, or 8 times per day. In particular embodiments, the patient
is administered the immediate release oxycodone in a dose, up to 6
times per day, that is equivalent to 1/6 of the oxycodone in the
daily dose.
[0084] In certain embodiments, the present disclosure provides a
method of normalizing bowel function in a patient on opioid therapy
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0085] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0086] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0087] In some embodiments, the present disclosure provides a
method of treating pain and normalizing bowel function in a patient
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0088] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0089] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0090] In some instances of the methods described above, the
patient is on opioid therapy prior to the method, for example from
administration of the daily dose or administration of other opioid
regimens. For example, the patient may have been on opioid therapy
for a certain time period, such as at least 2, 4, 6, 8, 10, 12, 18,
or 24 weeks or at least 1, 2, 3, 4, 6, or 8 months or at least 1,
1.5, 2, 2.5, or 3 years. In some embodiments, the opioid therapy
treats chronic pain of the patient. In certain embodiments,
administration of other opioid regimens include administration of
oxycodone, morphine, levorphenol, meperdine, hydrocodone, codeine,
dihydrocodeine, hydromorphone, propoxyphene, methadone,
oxymorphone, buprenorphine, or pharmaceutically acceptable salts of
any of these, or a combination thereof, particularly oxycodone or a
pharmaceutically acceptable salt thereof.
[0091] In other embodiments, the patient is not on opioid therapy
prior to the method, i.e., the patient is opioid naive.
[0092] In particular embodiments, the patient treated by the
methods described herein (e.g., by administration of the daily
dose) is suffering from cancer. The patient may be suffering from
pain derived from the cancer or derived from methods of treating
the cancer (such as chemotherapy and/or radiotherapy) or both. In
some embodiments, the present methods for treating pain (e.g.,
breakthrough or chronic pain) treat these types of pain associated
with cancer. In certain embodiments, the present methods for
improving bowel function, maintaining bowel function, or
normalizing bowel function comprise administering the daily dose to
the patient suffering from cancer.
[0093] In some embodiments, the present disclosure provides a
method of treating pain in a patient suffering from cancer
comprising orally administering to the patient a daily dose
comprising oxycodone or a pharmaceutically acceptable salt thereof
and naloxone or a pharmaceutically acceptable salt thereof in a 2:1
weight ratio;
[0094] wherein the daily dose comprises at least 90 mg of the
oxycodone or pharmaceutically acceptable salt thereof; and
[0095] wherein the daily dose is administered as two or more
prolonged release oral dosage forms.
[0096] In certain embodiments herein involving improving bowel
function, the improvement in bowel function is relative to that
experienced from administering a corresponding naloxone-free daily
dose (e.g., relative to placebo). For example, the improvement in
bowel function may be assessed by the difference in bowel function
index (BFI) scores between administering the daily dose and
administering a corresponding naloxone-free daily dose (e.g., each
relative to baseline). In certain instances, the difference in BFI
scores is at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20,
particularly at least 12, 14, 16, or 18, more particularly at least
12. In some embodiments, the difference in BFI scores is from 12 to
21, 12 to 20, 12 to 19, 12 to 18, or 12 to 17 or from 14 to 21, 14
to 20, 14 to 19, 14 to 18, or 14 to 17. In some instances, the
difference in BFI scores is at least 21, 22, 24, 26, 28, 30, 32,
33, or 34. In some embodiments, the difference in BFI scores is
from 12 to 22, 14 to 22, 16 to 22, or 18 to 22 or from 12 to 21, 14
to 21, 16 to 21, or 18 to 21.
[0097] In particular embodiments herein involving maintaining or
normalizing bowel function, the maintenance or normalization of
bowel function is relative to that experienced by a patient not on
opioid therapy, a patient who has not been administered an opioid,
or a non-constipated patient (but may have pain, such as chronic
pain); that is, the patient subsequent to treatment by the present
method exhibits bowel function levels similar to that of a patient
not on opioid therapy, a patient who has not been administered an
opioid, or a non-constipated patient. For example, the maintenance
or normalization of bowel function may be assessed by the
difference in BFI scores for the patient on opioid therapy (or
receiving the daily dose) and the patient not on opioid therapy or
not constipated. In certain instances, the difference in BFI scores
is equal to or less than 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3,
particularly equal to or less than 12, 10, 8, or 6, more
particularly less than 12. In some embodiments, the difference in
BFI scores is from 12 to 20, 12 to 19, 12 to 18, or 12 to 17 or
from 14 to 20, 14 to 19, 14 to 18, or 14 to 17.
[0098] In other embodiments, the maintenance or normalization of
bowel function may be assessed by comparing the BFI score for the
patient on opioid therapy (or receiving the daily dose) and known
BFI reference scores for subjects not on opioid therapy or not
constipated (see, e.g., Ueberall et al., J. Int. Med. Res. 39(1),
41-50 (2011), incorporated by reference herein). In certain
instances, the BFI for the patient on opioid therapy (or receiving
the daily dose) is less than 34, 32, 30, 29, 28, 27, 26, 25, 24,
23, 22, 21, or 20, such as less than 32, 30, 29, 27, or 25. In some
embodiments, the BFI for the patient on opioid therapy (or
receiving the daily dose) is from 20 to 32, 20 to 30, 20 to 29, 20
to 27, or 20 to 25.
[0099] In some embodiments, BFI scores are measured by taking the
mean symptom scores of two or three symptoms associated with bowel
function, such as defecation, feeling of incomplete bowel
evacuation, and judgment of constipation.
[0100] In certain embodiments, improving bowel function or
normalizing bowel function comprises reduction in the number or
hardness or dryness of stools; reduction of straining, bloating,
abdominal cramping, or abdominal distension associated with bowel
movements; reduction of gastric reflux or incomplete bowel
evacuation; and/or particularly reducing OIC.
[0101] In some embodiments, maintaining bowel function comprises
reducing or preventing an increase in the number or hardness or
dryness of stools; the amount of straining, bloating, abdominal
cramping, or abdominal distension associated with bowel movements;
the amount of gastric reflux or incomplete bowel evacuation; and/or
particularly the level of OIC.
[0102] In certain embodiments, administration of the daily dose in
the methods described herein provides analgesia to the patient.
[0103] In some embodiments, the methods described herein result in
a patient BFI score equal to or less than 45, 42, 40, 39, 38, 37,
36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, or 21,
particularly equal to or less than 35, 33, 31, or 29. In some
embodiments, the patient BFI score is from 21, 22, 23, 24, 25, 26,
27, or 28 to 33, 34, 35, 36, 37, 38, 39, 40, or 45, such as from 22
to 45, 22 to 42, 22 to 40, 22 to 38, or 22 to 35.
[0104] In certain embodiments, the daily dose comprises at least or
greater than 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,
200, 220, or 240 mg of oxycodone or pharmaceutically acceptable
salt thereof.
[0105] In some embodiments, the daily dose comprises from 90, 100,
110, 120, 130, 140, or 150 mg to 160, 170, 180, 190, 200, 210, 220,
230, or 240 mg oxycodone or a pharmaceutically acceptable salt
thereof. In certain embodiments, the daily dose comprises 90 mg to
480 mg, 90 mg to 240 mg, 90 mg to 200 mg, 90 mg to 180 mg, or 90 mg
to 160 mg oxycodone or a pharmaceutically acceptable salt thereof,
such as 100 mg to 480 mg, 100 mg to 240 mg, 100 mg to 200 mg, 100
mg to 180 mg, or 100 mg to 160 mg oxycodone or a pharmaceutically
acceptable salt thereof. In other embodiments, the daily dose
comprises 130 mg to 480 mg, 130 mg to 240 mg, 130 mg to 200 mg, 130
mg to 180 mg, or 130 mg to 160 mg oxycodone or a pharmaceutically
acceptable salt thereof.
[0106] In particular embodiments, the daily dose comprises 90, 100,
110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, or 240 mg
oxycodone or a pharmaceutically acceptable salt thereof,
particularly 100, 120, 140, 160, or 180 mg oxycodone or a
pharmaceutically acceptable salt thereof, in particular 120, 140,
or 160 mg oxycodone or a pharmaceutically acceptable salt
thereof.
[0107] The daily dose further comprises an amount of naloxone or
pharmaceutically acceptable salt thereof that is derivable from the
amount of oxycodone or pharmaceutically acceptable salt thereof in
the daily dose because the oxycodone and the naloxone are in a 2:1
weight ratio, respectively.
[0108] In certain embodiments, the daily dose is administered as
one prolonged release oral dosage form. In other embodiments, the
daily dose is administered as multiple prolonged release oral
dosage forms, i.e., two or more prolonged release oral dosage
forms, such as 2, 3, 4, 5, 6, 7, or 8 prolonged release oral dosage
forms, in particular as 2, 4, or 6 prolonged release oral dosage
forms. In some embodiments, the prolonged release oral dosage forms
have equal doses with respect to each other. In other embodiments,
the prolonged release dosage forms have unequal doses with respect
to each other.
[0109] In some embodiments, the daily dose is administered in two
administrations at approximately (e.g., within 60, 45, 30, 15. or 5
minutes) 12-hour intervals. In certain embodiments, the two
administrations comprise equal doses. In other embodiments, the two
administrations comprise different doses.
[0110] In preferred embodiments, the prolonged release oral dosage
form includes both the oxycodone or pharmaceutically acceptable
salt thereof and the naloxone or pharmaceutically acceptable salt
thereof. When the prolonged release oral dosage form includes both
the oxycodone and the naloxone, as noted above, the daily dose may
be administered as one prolonged release oral dosage form or as
multiple prolonged release dosage forms (e.g., 1, 2, 3, or 4 dosage
forms every 12 hours) to achieve the daily dose.
[0111] In other embodiments, the oxycodone or pharmaceutically
acceptable salt thereof and the naloxone or pharmaceutically
acceptable salt thereof are administered in separate prolonged
release oral dosage forms. Such a scenario necessarily requires
that the daily dose is achieved by administration of multiple
prolonged release oral dosage forms, e.g., dosage form(s) that
include the oxycodone and dosage form(s) that include the
naloxone.
[0112] In some embodiments, the daily dose is administered as two
prolonged release dosage forms, each administered at approximately
12-hour intervals. In other embodiments, the daily dose is
administered as four prolonged release dosage forms, with two of
the four prolonged release dosage forms administered at
approximately 12-hour intervals. In further embodiments, the daily
dose is administered as six prolonged release dosage forms, with
three of the six prolonged release dosage forms administered at
approximately 12-hour intervals. In other embodiments, the daily
dose is administered as eight prolonged release dosage forms, with
four of the eight prolonged release dosage forms administered at
approximately 12-hour intervals.
[0113] In certain embodiments, the daily dose is administered as
part of an on-going therapeutic regimen. For instance, in some
embodiments, the daily dose is administered daily for a period of
at least 2, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 24, 36, or 48
weeks, particularly, at least 4, 5, 8, or 24 weeks.
Definitions
[0114] In describing the present invention, the following terms are
used as indicated below.
[0115] As used herein, the singular forms "a", "an", and "the"
include plural references unless the context clearly indicates
otherwise.
[0116] The term "about" in the context of the present invention
denotes an interval of accuracy that a person skilled in the art
will understand to still ensure the technical effect of the feature
in question. The term typically indicates a deviation from the
indicated numerical value of .+-.10% and preferably .+-.5%.
[0117] The term "comprising" is not limiting. For the purposes of
the present invention, the term "consisting of" is considered to be
a preferred embodiment of the term "comprising". If hereinafter a
group is defined to comprise at least a certain number of
embodiments, this is also meant to encompass a group which
preferably consists of these embodiments only. The term "consisting
essentially of" is also considered to be a preferred embodiment of
the term "comprising".
[0118] The term "daily dose" as used herein refers to the amount of
oxycodone or pharmaceutically acceptable salt thereof and naloxone
or pharmaceutically acceptable salt thereof, which are administered
in combination within each 24-hour period according to the methods
disclosed herein. If, for example, the daily dose is stated as
comprising 90 mg to 200 mg of oxycodone or a pharmaceutically
acceptable salt thereof, this means that 90 mg to 200 mg of the
oxycodone or pharmaceutically acceptable salt thereof is
administered (with the corresponding amount of naloxone or a
pharmaceutically acceptable salt thereof) to the patient either in
a single administration step or in smaller amounts in multiple
administration steps resulting in total in the overall dose of 90
mg to 200 mg per day.
[0119] If reference is made to a specific daily dose comprising
oxycodone or a pharmaceutically acceptable salt thereof, e.g. 160
mg, and the oxycodone is administered in a dosage form or in
multiple dosage forms, which may further contain(s) the naloxone or
pharmaceutically acceptable salt thereof, the corresponding daily
dose of naloxone or pharmaceutically acceptable salt thereof will
be 80 mg because the oxycodone and the naloxone are in a 2:1 ratio
by weight, respectively. Such a daily dose maybe called a "160/80"
dose (oxycodone or pharmaceutically acceptable salt thereof to
naloxone or pharmaceutically acceptable salt thereof). If reference
is made herein to a "naloxone-free daily dose", this means that
naloxone is not co-administered but that only oxycodone is
administered in the given daily dose.
[0120] In the methods described herein, the weight ratio of the two
actives oxycodone or a pharmaceutically acceptable salt thereof and
naloxone or a pharmaceutically acceptable salt thereof is typically
2:1. In some embodiments, the weight ratio is calculated on the
basis of the free bases of the two actives (i.e., oxycodone free
base to naloxone free base). In other embodiments, the weight ratio
is calculated on the basis of the salts of the two actives, in
particular the hydrochloride salt of the two actives (i.e.,
oxycodone HCl to naloxone HCl). Unless stated otherwise, the weight
ratio is calculated on the basis of anhydrous variants of the two
actives (e.g., anhydrous oxycodone HCl to anhydrous naloxone HCl or
anhydrous oxycodone free base to anhydrous naloxone free base).
This does not mean that hydrates of one or both of the actives
cannot be used herein (e.g., naloxone HCl dihydrate), only that the
2:1 weight ratio is based on the corresponding amount of anhydrous
active(s). If the free bases are not comprised per se in the dosage
form(s), but rather as e.g. the hydrochloride salts or any other
salts, the amounts of the non-free base forms can routinely be
derived from the corresponding amounts of the free bases and vice
versa. Similarly, if anhydrous variants of the corresponding
actives are not used per se in the dosage form(s), but rather
hydrate(s), the amounts of the anhydrous form(s) can be routinely
derived from the corresponding amounts of the hydrates and vice
versa.
[0121] The term "bowel function" as used herein in particular but
not exclusively refers to opioid-induced bowel dysfunction (OIBD),
wherein OIBD comprises hard dry stools, straining, bloating,
abdominal cramping, abdominal distension, increased gastric reflux,
incomplete bowel evacuation and as the most distressing lead
symptom opioid-induced constipation (OIC). The term "maintaining
bowel function" refers to methods that maintain the patient's bowel
function ability (e.g., as measured by BFI score) at levels
described herein following the particular method. In contrast, the
term "normalizing bowel function" refers to methods that improve
the patient's bowel function ability (e.g., as measured by BFI
score)--which may have become reduced through opioid therapy or a
disease state (such as cancer or an intestinal disease)--to levels
described herein following the particular method.
[0122] The "BFI" score or "bowel function index" score as used
herein is described in detail e.g. in Rentz et al., J. Med. Econ.,
12(0), 371-383 (2009), incorporated herein by reference. As
disclosed in Rentz et al., 2009, a BFI score change of .gtoreq.12
points represents a clinically meaningful change, in particular for
OIC.
[0123] The term "pain" means moderate to severe, acute and chronic
pain of malignant and non-malignant origin, in particular severe to
most severe, acute and chronic pain of malignant and non-malignant
origin. In certain embodiments, methods of treating pain herein
include methods of treating cancer pain, i.e., pain derived from a
cancer or from a method of treating the cancer.
[0124] The term "patient" means a subject, particularly a human,
who has presented a clinical manifestation of a particular symptom
or symptoms suggesting the need for treatment, who is treated
preventatively or prophylactically for a condition, or who has been
diagnosed with a condition to be treated. The term "subject" is
inclusive of the definition of the term "patient" and does not
exclude individuals who are entirely normal in all respects or with
respect to a particular condition.
[0125] Whenever reference is made herein to a "difference in bowel
function index scores", this means that this difference is not to
be determined for a single patient, i.e. wherein the single patient
is administered the two different administration regimens under
comparison (in particular, one containing naloxone and one without
naloxone), but instead the difference in BFI scores is determined
between different patients. This can in particular be a patient
treated with oxycodone only vs. a patient treated with the
combination of oxycodone and naloxone, or results from previous
studies carried out with patients treated with oxycodone only.
[0126] The above definition also applies to the situation of a
patient treated with the combination of oxycodone and naloxone vs.
a patient not treated with an opioid or not on opioid therapy (such
as with e.g. oxycodone). Again, a difference is not to be
determined for a single patient, i.e. the single patient is
administered the two different administration regimens under
comparison (in particular, a combination of oxycodone and naloxone
and no opioid), but instead the difference in BFI scores is
determined between different patients. This can in particular be a
patient treated with the combination of oxycodone and naloxone vs.
a patient not treated with an opioid, or results from previous
studies carried out with patients not treated with opioids or not
on opioid therapy.
[0127] "Pharmaceutically acceptable salts" include, but are not
limited to, inorganic acid salts such as hydrochloride,
hydrobromide, sulfate, bisulfate, nitrate, phosphate and the like;
organic acid salts such as myristate, formate, acetate,
trifluoroacetate, maleate, malate, fumarate, succinate, tartrate,
bitartrate, and the like; sulfonates such as methanesulfonate,
benzenesulfonate, p-toluenesulfonate and the like; amino acid salts
such as arginate, asparaginate, glutamate and the like; metal salts
such as sodium salt, potassium salt, cesium salt and the like;
alkaline earth metals such as calcium salt, magnesium salt and the
like; and organic amine salts such as triethylamine salt, pyridine
salt, picoline salt, ethanolamine salt, triethanolamine salt,
discyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the
like.
[0128] A particularly preferred salt for both actives is the
hydrochloride salt. When the hydrochloride salt of naloxone is
used, it is even more preferred to use naloxone hydrochloride
dihydrate.
[0129] The oxycodone base and pharmaceutically acceptable salts
thereof may be present in solvent free form such as in the
anhydrous form, and as solvates such as the hydrates, and as
complexes, and mixtures thereof.
[0130] The naloxone base and pharmaceutically acceptable salts
thereof may be present in solvent free form such as in the
anhydrous form, and as solvates such as the hydrates, and as
complexes, and mixtures thereof.
[0131] PCT International Publication WO 2005/097801, U.S. Pat. No.
7,129,248, and U.S. Patent Application Publication 2006/0173029,
all of which are hereby incorporated by reference, describe
processes for preparing oxycodone hydrochloride having a
14-hydroxycodeinone level of less than about 25 ppm, preferably of
less than about 15 ppm, less than about 10 ppm, or less than about
5 ppm, more preferably of less than about 2 ppm, less than about 1
ppm, less than about 0.5 ppm or less than about 0.25 ppm.
[0132] The term "ppm" as used herein means "parts per million".
Regarding 14-hydroxycodeinone, "ppm" means parts per million of
14-hydroxycodeinone in a particular sample product. The
14-hydroxycodeinone level can be determined by any method known in
the art, preferably by HPLC analysis using UV detection.
[0133] In certain embodiments of the present invention, wherein the
active agent is oxycodone hydrochloride, oxycodone hydrochloride is
used having a 14-hydroxycodeinone level of less than about 25 ppm,
preferably of less than about 15 ppm, less than about 10 ppm, or
less than about 5 ppm, more preferably of less than about 2 ppm,
less than about 1 ppm, less than about 0.5 ppm or less than about
0.25 ppm.
The Prolonged Release Oral Dosage Form of the Present Invention
Amounts of the Actives in a Dosage Form According to the
Invention
[0134] It is preferred that a prolonged release oral dosage form of
the present invention comprises both actives, i.e. oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof. Generally, the dosage
form can comprise oxycodone or a pharmaceutically acceptable salt
thereof in an amount range of about 1 mg to about 240 mg, such as
about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 mg to
about 140, 150, 160, 180, 200, 220, or 240 mg. In certain
embodiments, the dosage form comprises oxycodone or a
pharmaceutically acceptable salt thereof in an amount range of
about 40 mg to about 240 mg, about 50 mg to about 240 mg, about 60
mg to about 240 mg, about 80 mg to about 240 mg, about 90 mg to
about 240 mg, about 120 mg to about 240 mg, or about 130 mg to
about 240 mg. In some embodiments, the dosage form comprises
oxycodone or a pharmaceutically acceptable salt thereof in an
amount range of about 40 mg to about 160 mg, about 50 mg to about
160 mg, about 60 mg to about 160 mg, about 80 mg to about 160 mg,
about 90 mg to about 160 mg, about 120 mg to about 160 mg, or about
130 mg to about 160 mg.
Particular Amounts of the Actives in a Dosage Form of the
Invention
[0135] In certain embodiments, the dosage forms comprise amounts of
equivalent to about 2.5 mg oxycodone HCl and about 1.25 mg naloxone
HCl; about 5 mg oxycodone HCl and about 2.5 mg naloxone HCl; about
10 mg oxycodone HCl and about 5 mg naloxone HCl; about 20 mg
oxycodone HCl and about 10 mg naloxone HCl; about 40 mg oxycodone
HCl and about 20 mg naloxone HCl; about 80 mg oxycodone HCl and
about 40 mg naloxone HCl; and about 100 mg oxycodone HCl and about
50 mg naloxone HCl. Even more preferred are amounts of 40 mg
oxycodone HCl and 20 mg naloxone HCl; 60 mg oxycodone HCl and 30 mg
naloxone HCl; 80 mg oxycodone HCl and 40 mg naloxone HCl; 100 mg
oxycodone HCl and 50 mg naloxone HCl; 120 mg oxycodone HCl and 60
mg naloxone HCl; 140 mg oxycodone HCl and 70 mg naloxone HCl; 160
mg oxycodone HCl and 80 mg naloxone HCl; and 180 mg oxycodone HCl
and 90 mg naloxone HCl.
Particular Daily Doses of the Invention
[0136] In some embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 90 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 40/20 dose and a 5/2.5 dose twice-a-day, or two
20/10 doses and a 5/2.5 dose twice-a-day, or a 30/15 dose and a
15/7.5 dose twice-a-day, such as approximately every 12 hours.
[0137] In certain embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 100 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 30/15 dose and a 20/10 dose twice-a-day, such as
approximately every 12 hours.
[0138] In some embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 120 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 60/30 dose twice-a-day, or two 30/15 doses
twice-a-day, such as approximately every 12 hours.
[0139] In certain embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 140 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 40/20 dose and a 30/15 dose twice-a-day, or a
60/30 dose and a 10/5 dose twice-a-day, such as approximately every
12 hours.
[0140] In some embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 160 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 80/40 dose twice-a-day, or two 40/20 doses
twice-a-day, such as approximately every 12 hours.
[0141] In certain embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 180 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 60/30 dose and a 30/15 dose twice-a-day, or a
80/10 dose and a 10/5 dose twice-a-day, such as approximately every
12 hours.
[0142] In some embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 200 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 60/30 dose and a 40/20 dose twice-a-day, such as
approximately every 12 hours.
[0143] In certain embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 220 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 80/40 dose and a 30/15 dose twice-a-day, such as
approximately every 12 hours.
[0144] In some embodiments, the present methods described herein
comprise administering a daily dose comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof in a 2:1 weight ratio,
wherein the daily dose comprises 240 mg of the oxycodone or
pharmaceutically acceptable salt thereof, and the daily dose is
administered as a 80/40 dose and a 40/20 dose twice-a-day, or two
60/30 doses twice-a-day, such as approximately every 12 hours.
Release Rates of the Two Actives from a Dosage Form of the Present
Invention
[0145] It is preferred that a dosage form comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salts thereof releases in vitro, when
measured using the Ph. Eur. Paddle Method at 50 rpm in 0.1 N
hydrochloric acid, pH 1.2 at 37.degree. C. and using UV detection
at 230 nm, about 5% to about 40% of oxycodone or a pharmaceutically
acceptable salt thereof by weight and about 5% to about 40% of
naloxone or a pharmaceutically acceptable salt thereof by weight at
15 min; about 20% to about 50% of oxycodone or a pharmaceutically
acceptable salt thereof by weight and about 20% to about 50% of
naloxone or a pharmaceutically acceptable salt thereof by weight at
1 hour; about 30% to about 60% of oxycodone or a pharmaceutically
acceptable salt thereof by weight and about 30% to about 60% of
naloxone or a pharmaceutically acceptable salt thereof by weight at
2 hours; about 50% to about 80% of oxycodone or a pharmaceutically
acceptable salt thereof by weight and about 50% to about 80% of
naloxone or a pharmaceutically acceptable salt thereof by weight at
4 hours; about 70% to about 95% of oxycodone or a pharmaceutically
acceptable salt thereof by weight and about 70% to about 95% of
naloxone or a pharmaceutically acceptable salt thereof by weight at
7 hours; and/or more than about 80% of oxycodone or a
pharmaceutically acceptable salt thereof by weight and more than
about 80% of naloxone or a pharmaceutically acceptable salt thereof
by weight at 10 hours.
[0146] In a particularly preferred embodiment relating to the in
vitro release of a prolonged release dosage form comprising
oxycodone or a pharmaceutically acceptable salt thereof and
naloxone or a pharmaceutically acceptable salts thereof, said
dosage form releases in vitro, when measured using the Ph. Eur.
Paddle Method at 50 rpm in 0.1 N hydrochloric acid, pH 1.2 at
37.degree. C. and using UV detection at 230 nm, about 10% to about
30% of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 10% to about 30% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 15 min; about 30% to about 45%
of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 30% to about 45% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 1 hour; about 40% to about 60%
of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 40% to about 60% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 2 hours; about 55% to about
70% of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 55% to about 75% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 4 hours; about 75% to about
90% of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 75% to about 90% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 7 hours; and/or more than
about 85% of oxycodone or a pharmaceutically acceptable salt
thereof by weight and more than about 85% of naloxone or a
pharmaceutically acceptable salt thereof by weight at 10 hours.
[0147] Further, in certain embodiments a prolonged release dosage
form according to the invention releases the oxycodone or a
pharmaceutically acceptable salt thereof and the naloxone or a
pharmaceutically acceptable salt thereof at substantially equal
release rates, such as with release rates that differ by 25% or
less, 20% or less, 15% or less, 10% or less, or 5% or less, for
example, when measured using the Ph. Eur. Paddle Method at 50 rpm
in 0.1 N hydrochloric acid, pH 1.2 at 37.degree. C. and using UV
detection at 230 nm.
[0148] The dosage form according to the present invention is
preferably administered on a twice-a-day basis and thus provides
its effect in vivo preferably for about 12 hours. However, it is
generally also possible to adapt the release rate such that a
once-a-day basis for the administration is achieved.
The Prolonged Release Dosage Form of the Present Invention
[0149] In general, all dosage forms providing a prolonged release
of the two actives may be used. Of course, a prolonged release
dosage form capable of providing the afore-mentioned in vitro
release rates is the most preferred prolonged release dosage
form.
[0150] In a preferred embodiment, the prolonged release dosage form
comprises a prolonged release matrix in order to achieve the
prolonged release. In an alternative preferred embodiment, the
prolonged release dosage form comprises a prolonged release coating
in order to achieve the prolonged release of the active agents. In
a further alternative preferred embodiment, the prolonged release
dosage form is an osmotic prolonged release dosage form. When a
prolonged release matrix dosage form is used, the matrix preferably
comprises a fatty alcohol and/or a hydrophobic polymer such as an
alkylcellulose with ethylcellulose being particularly preferred.
Other structural components of the different prolonged release
dosage forms are described below.
Further Features of the Dosage Form of the Present Invention
[0151] The dosage form of the present invention may comprise
further pharmaceutically acceptable ingredients and/or adjuvants,
such as e.g. lubricants, fillers, binders, flowing agents,
colorants, flavorants, surfactants, pH-adjusters, anti-tacking
agents and/or combinations thereof.
[0152] Preferably, the dosage form is selected from the group
consisting of a tablet, a capsule, a multiparticulate, a dragee, a
granulate, a liquid and a powder. A particularly preferred dosage
form is a tablet or a multi-particulate.
[0153] The dosage form according to the invention may comprise at
least one further pharmaceutically active agent providing a further
desired pharmaceutical effect in addition to the two active agents,
i.e. oxycodone or a pharmaceutically acceptable salt thereof and
naloxone or a pharmaceutically acceptable salt thereof. However, it
is preferred that the dosage form according to the invention
comprises the two actives oxycodone or a pharmaceutically
acceptable salt thereof and naloxone or a pharmaceutically
acceptable salt thereof as the sole pharmaceutically active
agents.
A Particular Dosage Form According to the Present Invention
[0154] It can be preferred that the dosage form is an oral
prolonged release dosage form comprising oxycodone or a
pharmaceutically acceptable salt thereof and naloxone or a
pharmaceutically acceptable salt thereof, wherein the two actives
are present in a weight ratio of 2:1 with amounts of oxycodone of
equivalent to 40, 60, or 80 mg oxycodone HCl (particularly 80 mg
oxycodone HCl) and of naloxone of equivalent to 20, 30, or 40 mg
naloxone HCl (particularly 40 mg naloxone HCl), wherein the dosage
form releases in vitro, when measured using the Ph. Eur. Paddle
Method at 50 rpm in 0.1 N hydrochloric acid, pH 1.2 at 37.degree.
C. and using UV detection at 230 nm, about 5% to about 40% of
oxycodone or a pharmaceutically acceptable salt thereof by weight
and about 5% to about 40% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 15 min; about 20% to about 50%
of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 20% to about 50% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 1 hour; about 30% to about 60%
of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 30% to about 60% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 2 hours; about 50% to about
80% of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 50% to about 80% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 4 hours; about 70% to about
95% of oxycodone or a pharmaceutically acceptable salt thereof by
weight and about 70% to about 95% of naloxone or a pharmaceutically
acceptable salt thereof by weight at 7 hours; and/or more than
about 80% of oxycodone or a pharmaceutically acceptable salt
thereof by weight and more than about 80% of naloxone or a
pharmaceutically acceptable salt thereof by weight at 10 hours.
[0155] In the dosage form employed herein, it is furthermore
preferred that the dosage form comprises oxycodone hydrochloride
and naloxone hydrochloride dihydrate. Although all prolonged
release dosage forms may be used, it is further most preferred that
the dosage form in its most preferred embodiment comprises a
prolonged release matrix.
The Release Behaviour of the Oral Dosage Form of the Present
Invention
[0156] In contrast to an "immediate release", a "prolonged release"
dosage form in accordance with the present invention refers to
pharmaceutical compositions which release in vitro .ltoreq.75% (by
weight) of the pharmaceutically active agents, namely oxycodone and
naloxone, at 45 min.
[0157] In the context of the present invention, the term "immediate
release" refers to pharmaceutical compositions showing a release of
the active substances which is not deliberately modified by a
special formulation design and/or manufacturing methods. For oral
dosage forms this means that the dissolution profile of the active
substances depends essentially on their intrinsic properties.
Typically, the term "immediate release" refers to pharmaceutical
compositions which release in vitro >75% (by weight) of the
pharmaceutically active agents at 45 min.
[0158] Prolonged release properties may be obtained by different
means such as by a coating which is then designated as a prolonged
release coating, a matrix which is then designated as a prolonged
release matrix or e.g. by an osmotic structure of the
pharmaceutical composition.
[0159] In order to obtain "prolonged release" properties, one
typically uses materials which are known to prolong the release
from a dosage form comprising e.g. a prolonged release matrix
and/or prolonged release coating. Typical examples are set out
further below. The nature of the "prolonged release material" may
depend on whether the release properties are attained by a
"prolonged release matrix" or a "prolonged release coating". The
term "prolonged release materials" thus describes both types of
materials. The term "prolonged release matrix material" indicates
that a material is used for obtaining a prolonged release matrix.
Likewise, the term "prolonged release coating material" indicate
that a material is used for obtaining a prolonged release
coating.
[0160] The term "prolonged release matrix formulation" refers to a
pharmaceutical composition including at least one prolonged release
material, and at least oxycodone and naloxone as the two
pharmaceutically active agents. In a "prolonged release matrix
formulation", the "prolonged release materials" are combined with
the pharmaceutically active agents to form a mixture from which the
pharmaceutically active agents are released over prolonged periods
of time, such as e.g. 8, 10, 12, 14, 16, 18, 20, 22 or 24
hours.
[0161] It is to be understood that a material will be considered to
act as prolonged release material if the dissolution profile of the
pharmaceutically active agents is slowed down compared to an
immediate or conventional release formulation. If a prolonged
release material can be used for manufacturing a prolonged release
matrix, it will be considered as a prolonged release matrix
material.
[0162] Pharmaceutically acceptable excipients which are used to
adjust an already prolonged release to a specific profile are not
necessarily considered to be prolonged release materials.
[0163] It is to be understood that a prolonged release matrix does
not necessarily consist only of the pharmaceutically active agents
and the prolonged release material. The prolonged release matrix
may comprise in addition pharmaceutically acceptable excipients
such as fillers, lubricants, glidants, etc. Examples of such
excipients are set out below.
[0164] The term "prolonged release coating formulation" refers to a
pharmaceutical composition including at least one prolonged release
material, and oxycodone and naloxone as the two pharmaceutically
active agents. In a "prolonged release coating formulation", the
"prolonged release materials" are disposed on the pharmaceutically
active agents to form a diffusion barrier. Other than in prolonged
release matrix formulation, the actives are not intimately mixed
with the prolonged release material and the prolonged release
coating does not form a three dimensional structure within which
the actives are distributed. As the term implies, the prolonged
release material forms a layer above the actives. The
pharmaceutically active agents are released from a prolonged
release coating formulation over prolonged periods of time, such as
e.g. 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
[0165] It is to be understood that a material will be considered to
act as prolonged release material if the dissolution profile of the
pharmaceutically active agents is slowed down compared to an
immediate or conventional release formulation. If a prolonged
release material can be used for manufacturing a prolonged release
coating, it will be considered as a prolonged release coating
material.
[0166] Pharmaceutically acceptable excipients which are used to
adjust an already prolonged release to a specific profile are not
necessarily considered to be prolonged release materials.
[0167] When it is mentioned that a prolonged release coating is
disposed on pharmaceutically active agents, this is not to be
construed as meaning that such a coating will necessarily be
directly layered on such active pharmaceutically agents. Of course,
if the pharmaceutically active agents, oxycodone and naloxone, are
layered on a carries such as Nu-Pareil beads, the coating may be
disposed directly thereon. However, the pharmaceutically active
agents may also be first embedded in a polymer layer or e.g. a
prolonged release matrix. Subsequently the prolonged release
coating may be disposed on e.g. granules which comprise a prolonged
release matrix or on tablets which are made from such granules by
compression for example.
[0168] A pharmaceutical composition with a prolonged release
coating may be obtained by combining the pharmaceutically active
agents with a carries such as Nu-Pareil beads and disposing a
prolonged release coating on said combinations. Such coating may be
made from polymers such cellulose ethers with ethyl cellulose being
preferred, acrylic resins, other polymers and mixtures thereof.
Such prolonged release coatings may comprise additional excipients
such as pore-formers, binders and the like.
[0169] It is further to be understood, that the term "prolonged
release matrix formulation" does not exclude pharmaceutical
compositions with a prolonged release matrix and an additional
prolonged release coating being disposed on the matrix. Likewise
the term "prolonged release coating formulation" does not exclude
pharmaceutical compositions with a prolonged release coating which
is disposed on prolonged release matrix.
[0170] The term "prolonged release dosage form" refers to the
administration form of a pharmaceutical composition of the present
invention comprising the two pharmaceutically active agents, i.e.
oxycodone and naloxone, in prolonged release form as e.g. in form
of a "prolonged release matrix formulation", in the form of a
"prolonged release coating formulation", combinations thereof or in
other prolonged release formulations such as osmotic formulations.
The terms "prolonged release matrix formulation" and "prolonged
release dosage form" can be used interchangeably if the prolonged
release dosage form consists essentially of the prolonged release
matrix formulation. This means that a prolonged release dosage form
can comprise in addition to the prolonged release matrix e.g.
cosmetic coatings and pharmaceutically acceptable excipients such
fillers, lubricants, etc.
[0171] For some embodiments, the term "prolonged release matrix
dosage form" may indicate that the dosage form comprises a
prolonged release matrix as the sole structure being responsible
for prolonging the release. This, however, does not exclude that
the dosage form may comprise an immediate release portion.
[0172] For some embodiments, the term "prolonged release coating
dosage form" may indicate that the dosage form comprises a
prolonged release coating as the sole structure being responsible
for prolonging the release. This, however, does not exclude that
the dosage form may comprise an immediate release portion.
[0173] The release rates indicated always refer to the formulation
such as a monolithic tablet or multi-particulates. The release
rates will be chosen such that a pharmaceutical composition can be
administered e.g. on a twice a day or once a day basis, i.e. every
12 hours or every 24 hours. Typically, the release will occur by
diffusion through the prolonged release matrix and/or coating,
erosion of the prolonged matrix and/or coating or combinations
thereof.
[0174] The term "substantially equal release rate" as used herein
means that the two active agents, i.e. oxycodone and naloxone, are
released from the dosage form such that their % of release does not
deviate by more than about 20%, preferably by not more than about
15% and most preferably by not more that about 10%. In the most
preferred embodiment, i.e. in the about 10% range, this means for
example for a prolonged release dosage form comprising oxycodone
and naloxone that if about 20% of oxycodone or a pharmaceutically
acceptable salt are released from the dosage form in vitro after 15
minutes, naloxone will be released within a range of about 10% to
about 30%, most preferably also at about 20% at 15 minutes.
Release Materials
[0175] The following description of suitable materials is to be
understood as being not limiting. Rather, the release material may
be any material that is known to be capable of imparting prolonged
release properties on the active agents, oxycodone and naloxone,
when being formulated into a dosage form.
Prolonged Release Matrix Materials
[0176] Suitable materials for inclusion in a prolonged release
matrix in order to provide a prolonged release matrix dosage form
comprising oxycodone and naloxone include: [0177] (a) Hydrophilic
or hydrophobic polymers, such as gums, cellulose ethers, acrylic
resins and protein derived materials. Of these polymers, the
cellulose ethers, especially alkylcelluloses are preferred. The
dosage form may conveniently contain between 1% and 80% (by weight)
of one or more hydrophilic or hydrophobic polymers. [0178] (b)
Substituted or unsubstituted hydrocarbons, such as fatty acids,
fatty alcohols, glycerol esters of fatty acids, oils, and waxes.
Hydrocarbons having a melting point of between 25 and 90.degree. C.
are preferred. The hydrocarbons may be long chain
(C.sub.8-C.sub.50, preferably C.sub.12-C.sub.40) hydrocarbons. The
hydrocarbons may be digestible. The oils and waxes may be
vegetable, animal, mineral or synthetic oils and waxes. Of these
hydrocarbon materials, fatty (aliphatic) alcohols are preferred.
The dosage form may conveniently contain up to 60% (by weight) of
at least one digestible, long chain hydrocarbon. [0179] (c)
Polyalkylene glycols. The dosage form may suitably contain up to
60% (by weight) of one or more polyalkylene glycols.
[0180] In a preferred embodiment, the pharmaceutical dosage forms
as described in the present invention will use a diffusion matrix
for achieving prolonged release of oxycodone and naloxone from the
pharmaceutical dosage form.
[0181] To this end, the diffusion matrix may be made from a
hydrophobic polymer and/or a C.sub.12-C.sub.36 fatty alcohol.
[0182] As regards the hydrophobic polymer, use of a hydrophobic
cellulose ether and particularly ethyl cellulose may be
preferred.
[0183] As regards the fatty alcohol, use of lauryl, myristyl,
stearyl, cetylstearyl, ceryl and/or cetylalcohol will be preferably
considered. The use of stearyl alcohol is particularly
preferred.
[0184] A particularly preferred embodiment relates to
pharmaceutical dosage forms in which the prolonged release
properties of oxycodone and naloxone are provided by a diffusion
matrix which is made from a hydrophobic polymer such as from ethyl
cellulose and a fatty alcohol. The matrices of some of the
preferred embodiments of the invention, which may e.g. be made from
the aforementioned combination of ethyl cellulose and stearyl
alcohol, will be a substantially non-swellable diffusion
matrix.
[0185] The term "substantially non-swellable diffusion matrix"
indicates that the matrix will be substantially non-erosive, i.e.
that the size of the matrix will not significantly increase upon
contact with fluids. Typically, the volume of a substantially
non-swellable diffusion matrix will increase at maximum up to 100%,
preferably at maximum up to 75%, more preferably at maximum up to
50%, even more preferably at maximum up to 25% and most preferably
at maximum up to 10% or at maximum up to 5% in volume upon
contacting an aqueous solution.
[0186] Pharmaceutical dosage forms which comprise a hydrophobic
polymer with hydrophobic cellulose ethers such as ethyl cellulose
being preferred as the sole or one of the components for providing
a prolonged release (non-swellable) diffusion matrix, will use an
amount of such polymer of between 5 to 20%, preferably of between 6
and 15% by weight and more preferably of between 7 to 10% by
weight. The percentages indicate the amount of the matrix-forming
material with respect to the total weight of the pharmaceutical
dosage form.
[0187] Pharmaceutical dosage forms, which comprise a fatty alcohol
as the sole or one of the components for providing a prolonged
release diffusion matrix, will use an amount of fatty alcohol in
the matrix of between 10 to 40%, preferably of between 15 to 35%
and more preferably of between 17 to 25% by weight. These
percentages again indicate the amount of fatty alcohol based on the
total weight of the dosage form.
[0188] The person skilled in the art is further aware that such a
prolonged release matrix may also contain other pharmaceutically
acceptable ingredients and excipients which are conventional in the
pharmaceutical art such as lubricants, fillers, binders, flowing
agents, colorants, flavorants, surfactants, pH-adjusters,
anti-tacking agents and granulating aids. These excipients will
typically have no substantial impact on the overall release
behavior of the pharmaceutical dosage form.
[0189] Typical examples of fillers (diluents) comprise lactose,
preferably anhydrous lactose, glucose, saccharose, starch and their
hydrolysates, microcrystalline cellulose, cellatose, sugar alcohols
such as sorbitol or mannitol, calcium salts like calcium hydrogen
phosphate, dicalcium- or tricalcium phosphate. Granulating aids
comprise inter alia povidone. Flowing agents and lubricants
comprise inter alia highly dispersed silica, talcum, magnesium
oxide, calcium stearate, magnesium stearate, sodium stearyl
fumarate, fast like hydrated castor oil and glyceryl dibehenate.
Binders can include hyproxypropylmethyl cellulose (hypromellose),
hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl
pyrollidone (povidone), acetic acid vinyl ester (copovidone) and
carboxymethycellulose sodium. Anti-tacking agents may include
glycerol monostearate. Furthermore, a matrix-based dosage form may
e.g. comprise a cosmetic coating.
Prolonged Release Coating Materials
[0190] As mentioned above, prolonged release characteristics of a
pharmaceutical dosage form may also be achieved by a film coating
that governs the release of the active agents from the dosage form.
To this end, the pharmaceutical dosage form may comprise a carrier,
which is associated with the opioid agonist and the opioid
antagonist. For example, one may use nonpareil beads, sugar beads
etc. on and/or into which the pharmaceutically active agents are
disposed.
[0191] Such active-associated carriers may then be overcoated with
a coating that provides prolonged release characteristics. Suitable
prolonged release coating materials include hydrophobic polymers
such as cellulose ethers and/or acrylic polymer resins.
Ethylcellulose may be preferred.
[0192] The prolonged release coatings may comprise other components
such as hydrophilic substances including hydrophilic polymers such
hydroxypropylmethylcellulose (HPMC), polyethylenglycols etc. These
components may be used to adjust the prolonged release
characteristics of the coatings. In case of e.g. HPMC, the
substances may act as pore formers. The coating may, of course,
also comprise additional pharmaceutically acceptable excipients,
e.g. as set out above for the matrices.
EXAMPLES
[0193] The present invention is now more fully described with
reference to the accompanying examples. It should be understood,
however, that the following description is illustrative only and
should not be taken in any way as a restriction of the
invention.
Example 1
[0194] Example 1 was a multicentre, multiple-dose, randomised,
double-blind, double-dummy, active-controlled, parallel-group study
in male and female subjects with non-malignant or malignant pain
requiring opioids to assess analgesic efficacy and symptoms of
constipation secondary to opioid treatment. The study was comprised
of three phases: a pre-randomization phase consisting of a
screening period and a run-in period, a double-blind phase and an
extension phase (FIG. 1). Eligible patients selected during the
screening phase entered the Run-in phase, during which OxyPR was
titrated to analgesic effect in order to determine the starting
dose to be used after randomization. At Visit 2 (V2), opioid
therapy was converted to open-label OxyPR and titrated to an
effective analgesic daily dose of OxyPR between 100-160 mg (50, 60,
70 or 80 mg twice daily). Patients were provided with
immediate-release oxycodone (Oxy IR) for breakthrough pain to be
used up to six times per day at a dose of approximately 1/6 that of
the total daily study medication, and oral bisacodyl 10 mg/day as
laxative rescue medication. Patients were also given a daily diary
to record analgesic rescue medication use, laxative rescue
medication use, bowel function measures, and average pain over last
24 hours. These patients had to be on a stable dose of OxyPR twice
daily for at least 4 consecutive days prior to randomization and
have a pain score of .ltoreq.4 with no more than two doses of Oxy
IR analgesic rescue medication per day for either the last 3
consecutive days or 4 of the last 7 days. Patients were randomly
assigned in a 1:1 ratio to OXN PR or OxyPR for up to 5 weeks. The
starting dose during the double-blind phase was dependent on the
effective, stable analgesic dose established in the run-in period,
but titration up to maximum daily dose of OXN PR 160/80 mg was
permitted after 1 week.
[0195] There were two primary endpoints, the first of which was to
demonstrate that patients taking OXN PR had improvement in symptoms
of constipation as measured by the Bowel Function Index (BFI)
compared with patients taking OxyPR tablets alone. The second was
to demonstrate non-inferiority of OXN PR compared with OxyPR with
respect to the analgesic efficacy based on average pain over last
24 hours as measured by the Pain Intensity Scale. Secondary
endpoints were analgesic and laxative rescue medication, complete
spontaneous bowel movements (CSBMs) and quality of life (EuroQol
EQ-5D).
[0196] Enrolled patients were males and females aged .gtoreq.18
years with cancer and non-cancer pain requiring opioids according
to World Health Organization (WHO) step III criteria and suffering
from opioid-induced constipation caused or aggravated by opioids.
Included patients were dissatisfied with their current analgesic
medication due to lack of efficacy or unacceptable tolerability.
The need for analgesic medication was defined as a documented
history of requiring around-the-clock opioid therapy (100-160 mg
OxyPR per day) for at least 5 weeks. Constipation caused or
aggravated by opioids was confirmed by the patient and the
investigator as an effect of the patient's pre-study opioid
medication (at a comparable dose) and evidenced by a medical need
of regular intake of laxatives to have at least three bowel
evacuations per week or by having less than three bowel evacuations
when not taking a laxative. Non-analgesic concomitant medications,
including those medications for the treatment of depression, and
the non-opioid analgesic medication dose were required to be stable
at screening and to have remained stable throughout the
double-blind phase of the study, as judged by the investigator.
Exclusion criteria included: history of hypersensitivity to
oxycodone, naloxone, related products or other ingredients of the
study medications; any contraindication to bisacodyl or any
components of the study medications; active alcohol or drug abuse
and/or history of opioid abuse; unreported illicit drug use
(including cannabis); any condition in which opioids are
contraindicated. Patients were also excluded if they had taken
naloxone .ltoreq.30 days prior to the start of the screening period
or at screening; if they were taking or had taken monoamine oxidase
inhibitors .ltoreq.2 weeks prior to the start of the screening
period; or if they were suffering from diarrhea.
[0197] Patients were assessed at weeks 1, 2, 4 and 5 during the
double-blind phase (at study site/home). Opioid-induced
constipation was assessed using the BFI, daily laxative rescue
medication use, and the number of CSBMs per week. The BFI score was
the mean of the following three items subjectively assessed by the
patient at each clinic visit: ease of defecation (numerical
analogue scale (NAS), 0=easy/no difficulty; 100=severe difficulty),
feeling of incomplete bowel evacuation (NAS, 0=not at all, 100=very
strong), and judgment of constipation (NAS, 0=not at all, 100=very
strong). Analgesic efficacy was measured as average pain over the
last 24 hours based on the Pain Intensity Scale (a numerical rating
scale 0-10 in which 0=no pain and 10=worst imaginable pain)
assessed at each visit and in patient daily diaries, together with
analgesic rescue medication use. Quality of life (QoL) was
evaluated using the EuroQol EQ-5D-3L instrument. Adverse events
were monitored throughout the 5-week study.
[0198] For the primary analysis of BFI endpoint, a mixed-model
repeated measures (MMRM) analysis of covariance of the BFI scores
was carried out with no missing data imputation. The repeated
measures analysis included fixed-effect terms for treatment and
time, random effect for centre or site, and pre-randomization value
at the end of the Baseline Period. The same statistical MMRM model
as used for the BFI was applied to analyse the Pain Intensity Scale
results for average pain over last 24 hours at each visit. The
superiority analysis on the BFI was performed using the FA
population and the non-inferiority test on the Pain Intensity Scale
was performed using the PP population. Superiority hypothesis tests
applied a 5% two-sided significance level, while non-inferiority
tests used a 2.5% one-sided significance level. All secondary
efficacy analyses were performed in an exploratory way using the
full analysis population. For analgesic rescue medication intake an
additional analysis on per protocol (PP) population was also
performed. Safety data were evaluated for all patients who received
study drug and for whom at least one post-dose safety assessment
was recorded. A subgroup analysis of all cancer patients (with or
without cancer-related pain) included in the study was conducted in
an exploratory manner providing descriptive statistics and
exploratory p-values to compare the treatment groups. All
statistical analyses were performed using SAS.RTM. version 9.3 or
later for Windows software package (SAS Institute, Cary, N.C.
27513).
[0199] A total of 363 patients were enrolled and screened at 66
clinical centers in 11 countries. Of these, 243 patients were
randomly assigned to treatment with OXN PR (n=123) or OxyPR
(n=120). In total, 209 patients completed the study: 105 patients
in the OXN PR group and 104 patients in the OxyPR group (FIG. 2).
After blinded subject evaluability review the following patient
populations were available for analysis in the two treatment
groups: full analysis, n=121 OXN PR and n=116 OxyPR; per protocol,
n=93 OXN PR and n=99 OxyPR; and safety, n=123 OXN PR and n=120
OxyPR. Baseline patient characteristics of the randomised
population are shown in Table 1:
TABLE-US-00001 TABLE 1 Baseline patient characteristics OXN PR
OxyPR Characteristic (n = 123) (n = 120) Age, mean (SD), 57.9
(11.03 [33-86]) 57.5 (12.33 [21-83]) range (years) Gender, n (%)
Male 53 (43.1) 47 (39.2) Female 70 (56.9) 73 (60.8) Weight, mean
(SD), 84.7 (21.45 [34-153]) 83.1 (21.09 [34-165]) range (kg) BMI,
mean (SD), range 29.2 (6.52 [14-47]) 28.3 (6.24 [17-50])
(kg/m.sup.2) Height, mean (SD), 170.0 (9.97 [150-196]) 169.6 (9.87
[150-196]) range (cm) BMI = body mass index.
[0200] Nearly all patients were taking at least one concomitant
medication. Just over half of patients (51.0%) were taking
medications for disorders of the alimentary tract and metabolism.
Consistent with the frequency of musculoskeletal and connective
tissue disorders, many patients were taking medications for
musculoskeletal symptoms. Non-steroidal anti-inflammatory and
anti-rheumatic agents were the most frequently used medications in
this therapeutic class.
[0201] The number of patients at each dosing level in the two
treatment groups were similar, with almost equal proportion of
patients at dose levels of 100 mg to 160 mg per day as shown in
Table 2:
TABLE-US-00002 TABLE 2 Number of patients (%) at each dose level
(full analysis population). Total population Cancer patients Dose
level OXN PR OxyPR OXN PR OxyPR (mg).sup.a (n = 121) (n = 116) (n =
28) (n = 22) 100 40 (33.1) 42 (36.2) 6 (21.4) 5 (22.7) 120 26
(21.5) 30 (25.9) 7 (25.0) 5 (22.7) 140 15 (12.4) 13 (11.2) 3 (10.7)
3 (13.6) 160 31 (25.6) 28 (24.1) 9 (32.1) 4 (18.2) Other 9 (7.4) 3
(2.6) 3 (10.7) 5 (22.7) .sup.aDose level defined as the highest
dose taken on more than 7 consecutive days. .sup.bNo specific dose
set for more than 7 consecutive days.
[0202] Bowel Function Index--Change in mean BFI scores from
baseline values (defined as Visit 3) during the 5 week double-blind
phase is shown in FIG. 3A. Reductions in baseline scores were
observed beginning at Week 1 and were greater in the OXN PR group
compared with the OxyPR group (-28.3 v -13.1). At Week 5 the mean
change from baseline continued to be greater in the OXN PR group
compared with the OxyPR group (-32.5 v -14.2). Based on the Mixed
Model Repeated Measures Analysis (MMRM) the difference between the
treatment groups was significant (LS mean difference (SE): -16.05
(3.14); p<0.001, CI: -22.23, -9.86). The difference was also
clinically meaningful and relevant being greater than 12 points
(Rentz et al., 2009).
[0203] The bowel function data were further analyzed based on the
different daily amounts of oxycodone administered, namely 100 mg
(Table 3), 120 mg (Table 4), 140 mg (Table 5) and 160 mg (Table 6).
As for the change in BFI scores from baseline for the above
mentioned OXN PR group compared with that of the OxyPR group, the
difference in the changes in BFI scores for the two groups were
greater than 12 for all tested doses as treatment progressed and
particularly by Week 5. In particular, the difference in the change
in mean BFI score at Week 5 between the OXN PR group the OxyPR
group was -16.1 (-31.7 v. -15.6) for the 100 mg dose, -20.1 (-32.7
v. -12.6) for the 120 mg dose, -16.8 (-37.1 v. -20.3) for the 140
mg dose and -19.9 (-31.2 v. -11.3) for the 160 mg dose. As noted
before, a difference of greater than 12 is clinically meaningful
and relevant (Rentz et al., 2009). These results include
differences significantly greater than 12, e.g., greater than 15,
16, 17, 18, 19 or even 20, and are therefore significantly
clinically meaningful.
TABLE-US-00003 TABLE 3 Summary of Bowel Function Index (BFI) by
Time point-Observed Values: Full Analysis Population/Dosing Class:
100 mg. OXN PR (N = 40) OxyPR (N = 42) Total (N = 82) Change from
Change from Change from Time point Value Baseline Value Baseline
Value Baseline Screening n 40 42 82 Mean (SD) 67.7 (16.40) 67.7
(16.80) 67.7 (16.50) Median 66.7 70.0 67.5 Min, Max 17, 97 27, 100
17, 100 Run-in n 40 42 82 Mean (SD) 67.4 (17.51) 65.8 (17.00) 66.6
(17.17) Median 66.7 67.5 66.7 Min, Max 17, 100 30, 100 17, 100
Baseline n 40 42 82 Mean (SD) 64.9 (22.37) 61.8 (24.45) 63.3
(23.37) Median 70.0 66.7 66.7 Min, Max 0, 100 0, 100 0, 100 Week 1
n 35 35 41 41 76 76 Mean (SD) 40.7 (24.43) -25.3 (22.43) 47.4
(27.62) -13.9 (20.32) 44.3 (26.24) -19.1 (21.93) Median 43.3 -20.0
53.3 -3.3 49.2 -10.0 Min, Max 0, 100 -85, 0 0, 90 -77, 7 0, 100
-85, 7 Week 2 n 40 40 41 41 81 81 Mean (SD) 38.5 (26.19) -26.4
(27.10) 46.0 (28.38) -15.7 (21.94) 42.3 (27.41) -21.0 (25.06)
Median 38.3 -21.7 50.0 -6.7 46.7 -13.3 Min, Max 0, 97 -87, 28 0, 90
-83, 15 0, 97 -87, 28 Week 4 n 39 39 40 40 79 79 Mean (SD) 34.3
(22.13) -30.0 (25.01) 45.3 (28.76) -16.5 (22.71) 39.9 (26.12) -23.2
(24.66) Median 30.0 -25.0 50.0 -10.0 43.3 -16.7 Min, Max 0, 90 -87,
3 0, 90 -77, 12 0, 90 -87, 12 Week 5 n 39 39 38 38 77 77 Mean (SD)
34.9 (23.89) -31.7 (25.67) 45.4 (28.46) -15.6 (20.20) 40.0 (26.60)
-23.8 (24.37) Median 33.3 -30.0 50.0 -10.0 43.3 -16.3 Min, Max 0,
90 -87, 7 0, 90 -77, 12 0, 90 -87, 12
TABLE-US-00004 TABLE 4 Summary of Bowel Function Index (BFI) by
Time point-Observed Values: Full Analysis Population/Dosing Class:
120 mg. OXN PR (N = 26) OxyPR (N = 30) Total (N = 56) Change from
Change from Change from Time point Value Baseline Value Baseline
Value Baseline Screening n 26 30 56 Mean (SD) 70.1 (11.79) 72.6
(20.69) 71.4 (17.04) Median 68.3 76.7 74.2 Min, Max 43, 97 7, 100
7, 100 Run-in n 26 30 56 Mean (SD) 69.2 (15.70) 70.5 (20.05) 69.9
(18.02) Median 70.0 71.7 70.0 Min, Max 38, 93 10, 100 10, 100
Baseline n 26 30 56 Mean (SD) 71.4 (15.49) 72.9 (16.29) 72.2
(15.80) Median 73.3 75.8 73.3 Min, Max 30, 97 40, 100 30, 100 Week
1 n 24 24 25 25 49 49 Mean (SD) 34.6 (21.75) -36.3 (24.61) 63.1
(18.22) -9.3 (21.31) 49.2 (24.48) -22.6 (26.53) Median 31.7 -38.3
70.0 -6.7 51.7 -20.0 Min, Max 0, 73 -82, 3 20, 93 -68, 23 0, 93
-82, 23 Week 2 n 25 25 30 30 55 55 Mean (SD) 35.4 (26.63) -36.7
(28.19) 61.1 (20.36) -11.8 (17.66) 49.4 (26.54) -23.1 (26.04)
Median 30.0 -40.0 69.2 -10.8 56.7 -20.0 Min, Max 3, 87 -80, 27 20,
92 -57, 22 3, 92 -80, 27 Week 4 n 22 22 26 26 48 48 Mean (SD) 36.9
(24.69) -36.0 (24.69) 62.5 (20.78) -11.5 (18.88) 50.8 (25.85) -22.7
(24.79) Median 30.8 -36.7 70.0 -6.7 60.0 -18.3 Min, Max 5, 85 -77,
2 18, 93 -57, 22 5, 93 -77, 22 Week 5 n 23 23 28 28 51 51 Mean (SD)
40.2 (28.72) -32.7 (27.39) 62.0 (25.69) -12.6 (26.56) 52.2 (28.98)
-21.7 (28.51) Median 30.0 -33.3 70.0 -5.8 60.0 -13.3 Min, Max 7, 97
-77, 13 5, 100 -80, 20 5, 100 -80, 20
TABLE-US-00005 TABLE 5 Summary of Bowel Function Index (BFI) by
Time point-Observed Values: Full Analysis Population/Dosing Class:
140 mg. OXN PR (N = 15) OxyPR (N = 13) Total (N = 28) Change from
Change from Change from Time point Value Baseline Value Baseline
Value Baseline Screening n 15 12 27 Mean (SD) 77.8 (19.98) 80.7
(14.24) 79.1 (17.40) Median 82.3 83.3 83.3 Min, Max 47, 100 53, 100
47, 100 Run-in n 15 13 28 Mean (SD) 78.8 (20.87) 72.9 (18.22) 76.1
(19.55) Median 85.0 76.7 78.3 Min, Max 37, 100 40, 100 37, 100
Baseline n 15 13 28 Mean (SD) 72.7 (16.54) 77.1 (16.86) 74.7
(16.53) Median 73.3 83.3 75.8 Min, Max 50, 100 43, 96 43, 100 Week
1 n 13 13 13 13 26 26 Mean (SD) 32.9 (23.39) -40.9 (33.86) 55.9
(26.48) -21.3 (27.08) 44.4 (27.13) -31.1 (31.67) Median 40.0 -33.3
50.0 -18.3 43.3 -21.7 Min, Max 0, 77 -100, 3 7, 100 -63, 17 0, 100
-100, 17 Week 2 n 15 15 12 12 27 27 Mean (SD) 34.0 (19.83) -38.7
(31.76) 58.2 (27.19) -19.5 (25.46) 44.8 (25.97) -30.2 (30.19)
Median 36.7 -40.0 53.3 -10.0 40.0 -20.0 Min, Max 0, 70 -100, 10 20,
100 -63, 7 0, 100 -100, 10 Week 4 n 14 14 11 11 25 25 Mean (SD)
33.3 (25.00) -40.7 (33.58) 50.3 (34.69) -29.9 (32.40) 40.8 (30.23)
-36.0 (32.83) Median 30.8 -37.5 60.0 -10.0 38.3 -20.0 Min, Max 0,
90 -100, 0 0, 95 -77, 0 0, 95 -100, 0 Week 5 n 14 14 10 10 24 24
Mean (SD) 36.5 (18.23) -37.1 (27.90) 61.6 (32.04) -20.3 (27.25)
47.0 (27.39) -30.1 (28.32) Median 36.7 -39.2 69.2 -6.7 45.8 -30.0
Min, Max 0, 70 -85, 17 0, 95 -70, 12 0, 95 -85, 17
TABLE-US-00006 TABLE 6 Summary of Bowel Function Index (BFI) by
Time point-Observed Values: Full Analysis Population/Dosing Class:
160 mg. OXN PR (N = 31) OXN PR (N = 28) OXN PR (N = 59) Change from
Change from Change from Time point Value Baseline Value Baseline
Value Baseline Screening n 31 28 59 Mean (SD) 75.7 (15.81) 65.1
(18.55) 70.7 (17.84) Median 76.7 66.7 73.3 Min, Max 20, 100 20, 93
20, 100 Run-in n 31 28 59 Mean (SD) 73.5 (15.02) 66.0 (18.33) 69.9
(16.96) Median 75.0 66.7 71.7 Min, Max 23, 100 20, 93 20, 100
Baseline n 31 28 59 Mean (SD) 69.9 (18.71) 61.8 (23.49) 66.0
(21.32) Median 70.0 63.3 68.3 Min, Max 10, 97 10, 100 10, 100 Week
1 n 27 27 24 24 51 51 Mean (SD) 49.9 (23.32) -20.9 (22.63) 50.4
(23.07) -11.4 (15.22) 50.2 (22.97) -16.4 (19.90) Median 53.3 -16.7
50.0 -6.7 53.3 -10.0 Min, Max 0, 90 -77, 20 0, 90 -53, 7 0, 90 -77,
20 Week 2 n 29 29 28 28 57 57 Mean (SD) 48.4 (19.17) -20.9 (21.91)
51.7 (21.74) -10.1 (16.30) 50.0 (20.36) -15.6 (19.94) Median 53.3
-16.7 55.0 -6.7 53.3 -13.3 Min, Max 0, 83 -78, 27 0, 90 -37, 23 0,
90 -78, 27 Week 4 n 28 28 26 26 54 54 Mean (SD) 43.8 (22.79) -25.1
(24.34) 53.2 (23.80) -8.6 (18.43) 48.3 (23.54) -17.2 (23.06) Median
41.7 -23.3 58.3 -6.7 50.0 -18.3 Min, Max 0, 93 -90, 37 0, 100 -53,
23 0, 100 -90, 37 Week 5 n 28 28 25 25 53 53 Mean (SD) 37.7 (24.99)
-31.2 (29.10) 48.6 (22.64) -11.3 (20.16) 42.9 (24.31) -21.8 (26.98)
Median 31.7 -25.0 50.0 -10.0 46.7 -15.0 Min, Max 0, 87 -93, 20 2,
100 -73, 27 0, 100 -93, 27
[0204] Pain scores--Average 24-hour pain scores were mild and
remained stable in the range 3-4 in both treatment groups (FIG. 4A)
and non-inferiority of OXN PR to OxyPR was confirmed as
statistically significant (p<0.001). Subgroup analyses by dose
level showed that subjects receiving 100-120 mg oxycodone per day
started with a mean pain score of 4.4 in the OXN PR group and 4.6
in the OxyPR group in the Run-in Phase (Table 7), which was almost
1 score lower than in patients receiving 140-160 mg/d, who had mean
pain scores of 5.4 in the OXN PR group and 5.1 in the OxyPR group.
However, pain scores at the beginning of the double-blind phase
(baseline) and at Week 5 were comparable in the subgroups, which
points to a greater level of pain relief in higher dose
subgroup.
TABLE-US-00007 TABLE 7 Sub-analysis of pain score according to dose
of OXN PR or OxyPR received. OXN PR OxyPR 100-200 mg/d 140-160 mg/d
100-200 mg/d 140-160 mg/d Time point (n = 60) (n = 33) (n = 64) (n
= 35) Run-in (n) 59 33 63 35 Mean (SD) 4.4 (1.8) 5.4 (1.6) 4.6
(1.9) 5.1 (1.8) Median (range) 4.0 (1-10) 5.0 (2-10) 4.0 (0-8) 5.0
(2-9) Baseline (n) 60 33 64 35 Mean (SD) 3.5 (0.79) 3.7 (0.53) 3.3
(1.03) 3.5 (0.78) Median (range) 4.0 (1-5) 4.0 (2-4) 4.0 (1-6) 4.0
(1-4) Week 5 (n) 60 33 62 32 Mean (SD) 3.6 (1.29) 3.6 (0.94) 3.4
(1.40) 3.5 (1.19) Median (range) 4.0 (0-6) 4.0 (1-6) 4.0 (0-7) 4.0
(1-6) Change from baseline (n) 60 33 62 32 Mean (SD) 0.2 (1.32)
-0.1 (0.70).sup. 0.0 (1.34) 0.1 (0.84) Median (range) .sup. 0.0
(-4-4) 0.0 (-1-2) .sup. 0.0 (-4-4) .sup. 0.0 (-3-2)
[0205] Analgesic rescue medication--Analgesic rescue medication
usage in the per protocol groups is shown in Table 8. Patients took
an average of <1 dose and between 10 and 15 mg Oxy IR as
analgesic rescue medication per day. No significant differences
between treatment groups were detected for frequency of dosing
(p=0.5145) or dose (p=0.4328) at Week 5.
TABLE-US-00008 TABLE 8 Analgesic and laxative rescue medication use
in the per population study groups for the overall study
populations and the cancer sub-group patients. Overall population
Cancer patients Time point OXN PR OxyPR OXN PR OxyPR Analgesic
rescue medication, mg/day* Baseline (n) 93 99 17 14 Mean (SD) 11.8
(14.7) 11.6 (15.7) 15.1 (19.7) 11.9 (15.2) Median (range) 6.4
(0-59) 4.6 (0-79) 7.1 (0-59) 4.5 (0-46) Week 5 (n) 93 99 17 14 Mean
(SD) 13.8 (16.4) 14.5 (18.8) 16.5 (18.3) 15.2 (17.4) Median (range)
6.7 (0-68) 3.0 (0-74) 14.3 (0-58) 11.1 (0-50) Laxative rescue
medication, mg/day.sup.+ Baseline (n) 121 116 27 19 Mean (SD) 1.8
(1.5) 1.5 (1.7) 1.5 (1.3) 2.5 (1.7) Median (range) 1.4 (0-7) 1.1
(0-9) 1.4 (0-4) 2.5 (0-6) Week 5 (n) 106 106 21 15 Mean (SD) 0.6
(1.1) 1.2 (1.7) 0.6 (1.1) 1.5 (2.3) Median (range) 0.0 (0-5) (0-7)
0.0 (0-4) 0.0 (0-6) *PP population. Time points are relative to
randomisation. .sup.+FA population. Time points are relative to
first intake of Double-blind IMP.
[0206] Laxative rescue medication--Laxative rescue medication use
in the full analysis population is also shown in Table 8. Patients
receiving OXN PR used significantly lower mean daily doses of
laxative rescue medication at Week 5 compared with those receiving
OxyPR as the mean (SD) values were 0.6 (1.1) vs 1.2 (1.7) mg/day
(p=0.006).
[0207] Complete Spontaneous Bowel Movement--The mean number of
CSBMs in the full analysis population increased to almost twice the
baseline value in the OXN PR group in Week 1 (1.5 to 2.8) while in
the OxyPR group a decrease was observed (2.1 to 1.5). An increase
in CSBM of 1 is considered clinically relevant. The mean number of
CSBMs remained stable through to Week 5 in the OXN PR group at 2.4
compared with 1.4 in the OxyPR group.
[0208] EuroQol EQ-5D--The overall EuroQol EQ-5D scores were similar
between the two treatment groups and showed a slight increase from
Run-in to Week 5. The mean (SD) scores in the OXN PR groups were
0.48 (0.28) and 0.60 (0.25) at baseline and Week 5, respectively.
These compare with the equivalent data of 0.45 (0.30) and 0.58
(0.27) for the OxyPR group.
[0209] Safety outcomes--Approximately 50% of patients experienced
at least one AE in either group (Table 9). Treatment-related AEs
with an incidence .gtoreq.1% are shown in Table 9. The most common
AE in either group was nausea. Four cancer patients died during the
study from causes unrelated to the study medication. Nine patients
in the OXN PR group and five patients in the OxyPR group
discontinued due to AEs.
TABLE-US-00009 TABLE 9 Summary of treatment-related adverse events
(AEs) occurring with an incidence of .gtoreq.1% (safety
population). Overall population Cancer patients OXN PR OxyPR OXN PR
OxyPR (n = 123) (n = 120) (n = 28) (n = 22) No. AEs 185 143 46 52
Patients with .gtoreq.1 AE, n (%) 67 (54.5) 57 (47.5) 18 (64.3) 15
(68.2) Patients with .gtoreq.1 treatment-related.sup.a AE, n (%) 47
(38.2) 29 (24.2) 7 (25.0) 5 (22.7) No. severe AEs 10 14 4 9
Patients with .gtoreq.1 severe AE, n (%) 10 (8.1) 9 (7.5) 4 (14.3)
5 (22.7) Patients with .gtoreq.1 treatment-related.sup.a severe AE,
n 8 (6.5) 5 (4.2) 2 (7.1) 2 (9.1) (%) Number of SAE 3 6 3 5
Patients with .gtoreq.1 SAE, n (%) 3 (2.4) 4 (3.3) 3 (10.7) 3
(13.6) Patients with .gtoreq.1 treatment-related.sup.a SAE, n (%) 0
0 0 0 Patients who died 1 (0.8) 3 (2.5) 1 (3.6) 3 (13.6) Most
frequent treatment-related.sup.a AEs, n (%): nausea 10 (8.1) 5
(4.2) 2 (7.1) 1 (4.5) hyperhidrosis 7 (5.7) 3 (2.5) 0 0 diarrhea 5
(4.1) 4 (3.3) 0 0 upper abdominal pain 4 (3.3) 4 (3.3) 0 0 drug
withdrawal syndrome 4 (3.3) 1 (0.8) 0 0 restlessness 4 (3.3) 1
(0.8) 0 0 dizziness 4 (3.3) 0 2 (7.1) 0 .sup.aInvestigator
considered the AE to be "unlikely", "possibly", "probably" or
"definitely" related to study medication. SAE = serious adverse
event. Data are n (%) unless stated otherwise.
[0210] Cancer patient sub-analysis--A total of 27 and 19 cancer
patients were treated in the OXN PR and OxyPR groups with the
number of patients at each dosing level (100 mg to 160 mg per day)
being comparable for the two groups (Table 2) analogous to the
overall population. Primary endpoint data for BFI (FIG. 3B) and
pain scores (FIG. 4B) reveal a similar pattern to that shown for
the total population (FIG. 3A and FIG. 4A). A MMRM analysis at Week
5 showed a clinically meaningful and statistically significant
treatment difference in BFI of -14.0 (8.1), p=0.047 in favour of
OXN PR. Pain scores remained at a low level throughout the study
and were comparable between groups. Rescue medication use is shown
in Table 8. No significant differences between treatment groups
were detected for frequency of analgesic rescue medication intake
(p=0.858) or dose (p=0.937) throughout the study. Patients
receiving OXN PR used slightly lower mean daily doses of laxative
rescue medication (0.8 mg) than those receiving OxyPR (p=0.269).
AEs including treatment-related AEs are shown in Table 9. Safety
profile was as expected in a population with severe illnesses and a
requirement for opioid analgesic treatment in the respective dose
range.
Example 2
[0211] Subjects who completed the 5-week Double-blind Phase, or
subjects who discontinued the Double-blind Phase prematurely due to
constipation, were eligible to enter the Extension Phase, which
consisted of additional 24 weeks treatment with open-label OXN PR
up to a maximum dose of 90/45 mg twice daily (i.e., 180/90 daily).
The extension phase was also open for subjects who required
continuation of daily opioid analgesic treatment and were likely to
benefit from chronic opioid therapy for the duration of the
extension phase. The results of this extension phase are described
in Example 2, wherein a particular focus was, in line with Example
1, on the assessment of bowel function and pain.
[0212] The Extension Phase duration was up to 24 weeks following
the Double-blind Phase plus one additional week Follow-up Period
(FIG. 1). In the Extension Phase, Subjects' non-malignant or
malignant pain that required around-the-clock opioid therapy was
treated with open-label study medication (i.e. OXN PR). All
subjects started the Extension Phase with the oxycodone PR dose
they had received at the end of the Double-blind Phase. The switch
from OXN PR or OxyPR at the end of the Double-blind Phase to
open-label OXN PR was done in a stepwise, double-blind,
double-dummy manner during the first week of the Extension Phase.
Medication titration was permitted at the discretion of the
Investigator from Visit 12 onwards. The subject's OXN PR dose could
be titrated to a maximum of OXN PR 90/45 mg twice daily.
Investigators could prescribe concomitant therapy, including
analgesic rescue medication and laxatives, as needed. Oxy IR and
bisacodyl were provided only for the first seven days of the
Extension Phase. Titration up to the maximum daily dose of OXN PR
90/45 mg twice daily was permitted from Visit 12 onwards. The
different dose levels were OXN PR 50/25 mg, OXN PR 60/30 mg, OXN PR
70/35 mg, OXN PR 80/40 mg and OXN PR 90/45 mg twice daily. Almost
all subjects who had completed the Double-blind Phase (195 of the
209 subjects) continued to the Extension Phase and 167 subjects
(85.6%) completed it.
[0213] Bowel Function Index--The BFI, which already had improved
throughout the Double-blind study, further decreased in the
Extension Phase (Table 10, FIG. 5). The greatest decrease was
already seen in the first week, when the mean (SD) BFI decreased
from 45.3 (26.37) to 30.8 (23.02). The mean (SD) BFI at the end of
the study was 26.7 (21.37) and the median was 25.0. Considering
that the BFI reference range for non-constipated patients with
chronic pain is 0-28.8 (Ueberall et al., 2011), this shows on
average a strong tendency for normalization of the bowel function
in this study. The subjects, who had received OxyPR in the
Double-blind phase started with a higher mean (SD) BFI of 53.6
(25.40) into the Extension Phase (Table 10, FIG. 6). These subjects
had a mean (SD) decrease by -25.9 (27.24) in the first week, to a
mean (SD) BFI score of 27.5 (23.43). At study end these subjects
had a mean (SD) BFI score of 23.7 (19.00), which is a change from
baseline of -30.4 (26.15). This was more than twice the clinical
relevance limit, which is reached by a decrease of 12 (Rentz et
al., 2009). Subjects who had already received OXN PR in the
Double-blind Phase, and who already started the Extension Phase
with an improved bowel function, showed a further decrease in mean
(SD) BFI from 37.5 (24.95) at the start of the Extension Phase to
33.9 (22.32) after the first week and to 29.5 (23.12) at the end of
the study. This amounts to an overall decrease of -8.3 (24.77).
These results show that the onset of the naloxone effect in
patients with opioid-induced bowel dysfunction occurs in the first
week of treatment, and an improvement of bowel function continues
and is maintained under long-term treatment with OXN PR.
[0214] The improvements in bowel function in subjects who initiated
OXN PR treatment in the Extension Phase mirrors and confirms the
improvement of the bowel function observed in the OXN PR group in
the Double-blind Phase, which had decreased in the mean by -28.3
(25.67) in the first week (see Example 1). The improved bowel
function--in subjects who were switched to OXN PR at the beginning
of the Double-blind Phase as well as subjects who were switched at
the beginning of the Extension Phase--improved further and was
maintained throughout the duration of the Extension Phase.
[0215] Pain scores--The subjects' average pain over the last 24
hours was measured by the Pain Intensity Scale (NRS 0-10), with 0
meaning no pain and 10 meaning worst imaginable pain. Pain
assessments were documented on Visits 11-19. The assessment at
Visit 11 served as the baseline for the later pain assessments. The
average pain over the last 24 hours remained stable on a low score
over the whole period of 24 weeks (FIG. 7). The median pain score
was 4.0 throughout the study, in subjects who had received OxyPR in
the Double-blind Phase as well as subjects who remained on OXN PR.
The overall mean pain score over 24 hours was 3.6 at baseline, and
remained between 3.8 and 4.0 throughout the study.
[0216] All the subgroups showed the same pattern. No clinically
relevant differences were observed between the subgroups, showing
comparable analgesic efficacy in younger, older, male and female
patients, and in every dose level from 100/50 mg OXN PR to 180/90
mg OXN PR. The pain was stable with minimal changes to baseline. In
particular, there was no clinically relevant difference between the
dosing subgroups. In the 100-120 mg dose level subgroup the mean
(SD) pain score was 3.6 (1.11) at baseline, 3.9 (1.44) after 1 week
and 3.7 (1.17) after 24 weeks. In the 140-160 mg dose level
subgroup the mean (SD) pain score was 3.7 (1.16) at baseline, 3.9
(1.39) after 1 week and 3.9 (1.45) after 24 weeks. In the >160
mg dose level subgroup the mean (SD) pain score was 3.9 (1.03) at
baseline, 4.5 (1.41) after 1 week and 4.4 (1.85) after 24
weeks.
[0217] Safety outcomes--A total of 128 subjects (65.6%) experienced
452 AEs, of which 162 in 57 subjects (29.2%) were assessed as
causally related to study medication, and 39 in 28 subjects (14.4%)
were severe. Twenty-one (21) subjects (10.8%) experienced 36 SAEs,
of which 13 SAEs in 6 subjects (3.1%) were assessed as causally
related to study medication by the investigator. Four subjects
(2.1%) died of unrelated SAEs. More AEs and more related AEs
occurred in the week after the switch from OxyPR to OXN PR (70 AEs
in 35 subjects, of which 45 AEs in 19 subjects were causally
related to study medication) than after the switch from OXN PR in
the Double-blind Phase to OXN PR in the Extension Phase (19 AEs in
14 subjects, of which 6 AEs in 5 subjects were causally related to
study medication). This was an expected observation, as the onset
of the naloxone effect on the intestinal mobility is likely to be
associated with gastrointestinal events like diarrhea.
[0218] The latter statement is confirmed by the short duration of
this effect, as in Weeks 2 to 4 and Weeks 5 to 24, the differences
between subjects formerly in the OXN PR and subjects formerly in
the OxyPR group had levelled out. In Weeks 2 to 4, 25 subjects
(25.0%) previously treated with OXN PR experienced 52 AEs of which
20 were related, and 19 subjects (20.9%) previously treated with
OxyPR experienced 36 AEs of which 21 were causally related to study
medication. In Weeks 5 to 24, 48 subjects (50.0%) previously
treated with OXN PR experienced 142 AEs of which 44 were causally
related to study medication, and 42 subjects (47.2%) previously
treated with OxyPR experienced 96 AEs of which 20 were causally
related to study medication. Despite the greater number of subjects
experiencing AEs in Weeks 5 to 24, this points to a decrease in AE
rate throughout the study, as the total incidence of AEs declined
from 25.1% in the first week to 23.0% over a period of 3 weeks (a
rate of 7.7% per week) and to 48.6% over a period of 20 weeks (a
rate of 2.4% per week). These results show that long-term use of
OXN PR in doses of 100/50 mg to 180/90 mg per day is not associated
with an increased safety risk.
[0219] The most frequently observed AEs were pain in 16 (8.2%)
subjects, diarrhea in 15 (7.7%) subjects, headache in 13 (6.7%)
subjects, constipation and nausea in 12 (6.2%) subjects each, and
hyperhidrosis in 11 (5.6%) subjects. All these AEs are known
adverse reactions of OXN PR and other strong opioids. Pain--though
not an AE subsequent to OXN PR administration--is an expected AE in
a population with severe pain conditions at any point in time due
to fluctuations of their underlying disease. With regards to system
organ classes, most AEs were observed in the gastrointestinal
disorders SOC, with 50 (25.6%) subjects experiencing 82
gastrointestinal AEs. In the first week 16 (8.2%) subjects
experienced gastrointestinal AEs, 13 of whom had been switched from
OxyPR. The most frequent AEs in these 13 subjects were diarrhea in
7 subjects, nausea in 4 subjects and upper abdominal pain in 3
subjects. All these AEs point to an onset of the gastrointestinal
action of the naloxone within OXN PR in those oxycodone pre-treated
subjects. In Weeks 2 to 4, 11 subjects (5.8%) experienced
gastrointestinal AEs, of whom 5 were from the former OXN PR and 6
from the former OxyPR group. In Weeks 5 to 24, 26 subjects (14.1%)
experienced gastrointestinal AEs, 18 subjects from the former OXN
PR group and 8 subjects from the former OxyPR group; this is a mean
rate of 0.7% of subjects who experienced gastrointestinal AEs per
week. A total of 14 subjects experienced diarrhea (reporting 15
events): 1 subject at 90 mg and at 160 mg, 3 subjects at 100 mg, 3
subjects at 120 mg, 2 subjects at 140 mg, 4 subjects at 160 mg, 1
subject at 180 mg.
TABLE-US-00010 TABLE 10 Summary of Bowel Function Index (BFI) by
Time point-Observed Values: Total Exposure Safety Population.
Double-blind Medication Extension Phase OXN PR OxyPR Total (N =
100) (N = 95) (N = 195) Time Change from Change from Change from
point Value Baseline Value Baseline Value Baseline Baseline n 100
95 195 (T1) Mean (SD) 37.5 (24.95) 53.6 (25.40) 45.3 (26.37) Median
33.3 58.3 50.0 Min, Max 0, 97 0, 100 0, 100 Week 1 n 100 100 92 92
192 192 (T2) Mean (SD) 33.9 (22.32) -3.6 (16.09) 27.5 (23.43) -25.9
(27.24) 30.8 (23.02) -14.3 (24.74) Median 30.0 0.0 26.7 -20.0 26.7
-5.8 Min, Max 0, 95 -68, 37 0, 90 -90, 23 0, 95 -90, 37 Week 2 n 96
96 89 89 185 185 (T3) Mean (SD) 32.7 (24.35) -3.5 (19.94) 27.5
(22.95) -26.6 (28.23) 30.2 (23.77) -14.6 (26.84) Median 30.0 0.0
23.3 -23.3 26.7 -6.7 Min, Max 0, 95 -80, 57 0, 94 -92, 32 0, 95
-92, 57 Week 4 n 96 96 89 89 185 185 (T4) Mean (SD) 32.3 (24.24)
-4.1 (21.39) 26.4 (21.68) -27.7 (26.54) 29.5 (23.17) -15.5 (26.69)
Median 30.0 -3.3 23.3 -26.7 26.7 -10.0 Min, Max 0, 100 -77, 52 0,
87 -92, 30 0, 100 -92, 52 Week 8 n 96 96 86 86 182 182 (T5) Mean
(SD) 30.2 (22.78) -6.3 (20.52) 25.2 (19.77) -28.5 (26.65) 27.8
(21.50) -16.8 (26.06) Median 26.7 -3.3 23.3 -29.2 25.0 -11.7 Min,
Max 0, 90 -83, 47 0, 80 -92, 30 0, 90 -92, 47 Week 12 n 94 94 84 84
178 178 (T6) Mean (SD) 28.5 (20.87) -7.8 (22.43) 26.4 (21.95) -27.4
(30.23) 27.5 (21.35) -17.1 (28.09) Median 26.7 -3.3 23.3 -27.5 24.2
-11.7 Min, Max 0, 100 -87, 50 0, 90 -95, 73 0, 100 -95, 73 Week 16
n 91 91 82 82 173 173 (T7) Mean (SD) 30.5 (21.74) -6.6 (23.25) 24.3
(20.68) -30.1 (28.98) 27.6 (21.41) -17.7 (28.57) Median 28.3 -3.3
21.7 -29.2 25.0 -11.7 Min, Max 0, 95 -83, 57 0, 80 -95, 60 0, 95
-95, 60 Week 20 n 89 89 81 81 170 170 (T8) Mean (SD) 27.6 (21.88)
-9.2 (23.83) 23.2 (19.31) -31.3 (27.17) 25.5 (20.75) -19.7 (27.71)
Median 23.3 -5.0 21.7 -30.0 23.3 -14.2 Min, Max 0, 97 -90, 48 0, 73
-95, 27 0, 97 -95, 48 Week 24 n 85 85 79 79 164 164 (T9) Mean (SD)
29.5 (23.12) -8.3 (24.77) 23.7 (19.00) -30.4 (26.15) 26.7 (21.37)
-18.9 (27.68) Median 25.0 -3.3 23.3 -26.7 25.0 -13.3 Min, Max 0,
100 -85, 60 0, 80 -95, 27 0, 100 -95, 60 N = Number of subjects in
population. n = Number of subjects with available data. SD =
Standard Deviation. Time points are relative to first intake of
extension phase study medication (IMP). Baseline defined as Visit
11.
Example 3
[0220] Exemplary suitable tablets are twice-a-day 60/30 and 80/40
OXN tablets. Administration of one of these tablets every 12 hours
results in a daily dose of oxycodone of 120 mg (60 mg of naloxone)
and of 160 mg (80 mg of naloxone), respectively. The compositions
of the tablet cores are given in the following, wherein such cores
are usually coated by a cosmetic coating (i.e. the coating will not
influence the release of the actives from the tablets).
TABLE-US-00011 Tablet 60/30 Ingredient Amount (mg) Oxycodone HCI,
anhydrous (60.00) corresponding to Oxycodone HCI .sup.1 63.00
Naloxone HCI, anhydrous (30.00) corresponding to Naloxone 32.70
hydrochloride dihydrate Polyvinylpyrrolidone 14.50 Lactose
monohydrate 77.10 Ethyl cellulose 24.00 Stearyl alcohol 59.00 Talc
5.00 Mg-Stearate 2.50 Core weight 277.80 .sup.1 calculated based on
expected moisture content
TABLE-US-00012 Tablet 80/40 Ingredient Amount (mg) Oxycodone HCI,
anhydrous (80.00) corresponding to Oxycodone HCI .sup.1 84.00
Naloxone HCI, anhydrous (40.00) corresponding to Naloxone 43.60
hydrochloride dihydrate Polyvinylpyrrolidone 14.50 Lactose
monohydrate 45.20 Ethyl cellulose 24.00 Stearyl alcohol 59.00 Talc
5.00 Mg-Stearate 2.50 Core weight 277.80 .sup.1 calculated based on
expected moisture content
[0221] Additional dosage forms suitable for use in the methods
described herein are disclosed in WO 2012/020097, the entire
contents of which are incorporated by reference.
[0222] All patent and non-patent references cited herein are
incorporated by reference.
* * * * *